Chemical compounds

ABSTRACT

The present disclosure describes novel compounds, or their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their medical uses. The compounds of the disclosure have activity as prostaglandin EP4 receptor antagonists, and are useful in the treatment or alleviation of pain and inflammation and other inflammation-associated disorders, such as arthritis, treating or preventing disorders or medical conditions selected from pain, inflammatory diseases and the like. Also described herein are methods of treating pain by administering the compounds of the disclosure, which are EP4 receptor antagonists.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. ProvisionalApplication Ser. No. 62/798,738, filed Jan. 30, 2019, hereinincorporated by reference in its entirety

FIELD OF THE INVENTION

The present disclosure describes novel compounds, or theirpharmaceutically acceptable salts, pharmaceutical compositionscontaining them, and their medical uses. The compounds of the disclosurehave activity as prostaglandin EP4 receptor antagonists, and are usefulin the treatment or alleviation of pain and inflammation and otherinflammation-associated disorders, such as arthritis, treating orpreventing disorders or medical conditions selected from pain,inflammatory diseases and the like. Also described herein are methods oftreating pain by administering the compounds of the disclosure, whichare EP4 receptor antagonists.

BACKGROUND

Rheumatoid arthritis (RA) is an immune-mediated, systemic inflammatorydisease that affects mainly synovial joins, with intra-articularinflammation, synovial hyperplasia and progressive degradation ofcartilage and bone. Prevalence of the disease is about 1% of thepopulation, and the disease is more frequent (and perhaps worse) inwomen than in men. There have been clear advances in the pharmacologicalmanagement of rheumatoid arthritis over the last decade, but manypatients still do not tolerate or do not respond well to the availabletherapies.

Moreover, the control and management of arthritis associated pain andinflammation in animals, such as companion animals, specifically indogs, is also an area of growing interest. Many FDA-approved drugs areavailable to treat pain associated with osteoarthritis (OA) in dogs(e.g., carprofen, firocoxib, meloxicam, deracoxib, and robenacoxib), allof which work by inhibiting cyclooxygenase enzymes. The FDA approved COXinhibitor NSAIDs for use in dogs, unless contra-indicated, areconsidered to be effective treatments for the pain associated with RA.These COX-inhibiting NSAIDs, as a class, however, carry the potentialfor adverse effects including gastrointestinal ulceration andperforation, and renal insufficiency. The Food and Drug Administration(FDA) has required language in the precaution section of the packageinserts of these drugs warning that, as a class, they may be associatedwith renal, gastrointestinal (GI), and hepatic toxicity. Specifically,labels of these drugs warn of the “potential to produce GI ulcerationand/or GI perforation”.

Prostaglandins are mediators of pain, fever and other symptomsassociated with inflammation. Especially prostaglandin E2 (PGE2) is thepredominant eicosanoid detected in inflammation conditions. In addition,it is also involved in various physiological and/or pathologicalconditions and such as hyperalgesia, uterine contraction, digestiveperistalsis, awakeness, suppression of gastric acid secretion, bloodpressure, platelet function, bone metabolism, angiogenesis or the like.

Four PGE2 receptor subtypes (EP1, EP2, EP3 and EP4) displaying differentpharmacological properties have been cloned. EP4 subtype, a Gs-coupledreceptor stimulates cAMP production, and is distributed in a widevariety of tissue suggesting a major role in PGE2-mediated biologicalevents.

Among the multiple targets involved in the pathogenesis of rheumatoidarthritis, the prostaglandin E2 receptor 4 (EP4) subtype receptor ofprostaglandin E2 (PGE2) is one of the most promising because, unlikecommon NSAIDs that inhibit the synthesis of prostaglandins, selectiveEP4 antagonists have the potential to combine immunomodulatory anddirect anti-inflammatory properties. Furthermore, the EP4 receptor inmice, humans and dogs has been cloned and characterized and the canineEP4 receptor has approximately 90% homology to the human receptor. EP4antagonists present an opportunity for a novel pharmaceutical orveterinary therapy.

Grapiprant, whose chemical name isN-[[[2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl]amino]carbonyl]-4methylbenzenesulfonamide, and sold under the tradename Galliprant®, is aprostaglandin E2 (PGE2) EP4 receptor antagonist; a non-cyclooxygenase(COX) inhibiting, non-steroidal anti-inflammatory drug (NSAID) in thepiprant class. Grapiprant is indicated for the control of pain andinflammation associated with osteoarthritis (OA) in dogs. Furtherreference is made to WO 2002/032422, WO 2002/032900, WO 2006/095268, aswell as WO 2003/086371, WO 2011/102149, and WO 2014/148053. Additionalbackground research regarding compounds with an imidazopyridine orimidazopyrazine core ring structure include US 2013/195848, WO2014/078813, WO 2011/151259, WO 2011/113862, US 2005/0009832, US2004/0220189, WO 2006/091671, and WO 2018/013430. All of these citedpatent publications are incorporated by reference with regard to theirbackground teaching.

Despite this background of research and development, there remains aneed for novel EP4 antagonists to offer safe and effectivepharmaceutical or veterinary therapy. PCT/US2018/046142, hereinincorporated by reference in its entirety, describes novelimidazopyridine/pyrazine derivatives with activity as prostaglandin EP4receptor antagonists. More specifically, the imidazopyridine/pyrazinederivatives, including veterinary or pharmaceutically acceptable saltsthereof, are represented by Formula (I):

whereinX is N or CR¹, where each R¹ individually is hydrogen, halogen, CN, C₁₋₃alkyl, or C₁₋₃ haloalkyl;R² is hydrogen, C₁₋₃ alkyl, or C₁₋₃ haloalkyl;R³ is hydrogen, C₁₋₃ alkyl, or C₁₋₃ haloalkyl;R⁴ is hydrogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl, or C₃₋₆ cycloalkyl;R⁵ is hydrogen, halogen, CN, C₁₋₃ alkyl, or C₁₋₃ haloalkyl;Ar is phenyl, pyridyl, or thiophenyl, each optionally substituted withone or more halogen, CN, NO₂, NH₂, N(C₁₋₃ alkyl)₂, OH, OC₁₋₃ alkyl, C₁₋₃alkyl, or C₁₋₃ haloalkyl; andL is —CH₂CH₂—, —CH₂CH₂CH₂—, or —OCH₂CH₂—.

One embodiment described is a compound1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea, or a veterinary or pharmaceutically acceptable salt thereof.

SUMMARY

The present disclosure describes compounds according to Formula (II), ora veterinary or pharmaceutically acceptable salt thereof:

whereinX is N or CR¹, where each R¹ individually is hydrogen, halogen, CN, C₁₋₃alkyl, or C₁₋₃ haloalkyl;R² is hydrogen, halogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, aryl, orheteroaryl;R³ is hydrogen, halogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl, or CN;R⁴ is hydrogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl,heterocyclyl, heteroaryl, or aryl;Z is phenyl or C₃₋₇ cycloalkyl, each substituted with one or more R⁵,where R⁵ is hydrogen, halogen, CN, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃haloalkoxy, or C₁₋₃ alkoxy;Ar is phenyl, pyridyl, or thiophenyl, each optionally substituted withone or more halogen, CN, NO₂, NH₂, N(C₁₋₃ alkyl)₂, OH, C₁₋₃ alkoxy, C₁₋₃alkyl, or C₁₋₃ haloalkyl;L is —CH₂CH₂—, —CH₂CH₂CH₂—, or —OCH₂CH₂—; andn is 0 or 1.

As depicted, the group Ar may be attached to theimidazopyridine/pyrazine core and to the group L in any arrangement. Inone embodiment, the imidazopyridine/pyrazine core is located para to thegroup L. In one embodiment, the group Ar is phenyl and the group L isarranged para to the imidazopyridine/pyrazine core; as will beappreciated, depending on numbering, namely a 1,4 arrangement. In oneembodiment, the group Ar is pyridyl and the L group is arranged para tothe imidazopyridine/pyrazine core; as will be appreciated, depending onnumbering, namely a 2,5 or 3,6 arrangement. In one embodiment, the groupAr is thiophene and the group L is located, depending on numbering,namely a 2,4, 2,5, or 3,5 arrangement.

In one embodiment, the disclosure includes the compounds of Formula (II)wherein X is N.

In one embodiment, the disclosure includes the compounds of formula (II)wherein R² is C₁₋₃ alkyl.

In one embodiment, the disclosure includes the compounds of formula (II)wherein R³ is C₁₋₃ alkyl.

In one embodiment, the disclosure includes the compounds of formula (II)wherein R⁴ is C₁₋₃ alkyl or C₁₋₃ haloalkyl.

In one embodiment, the disclosure includes the compounds of formula (II)wherein R⁵ is C₁₋₃ alkyl or halogen.

In one embodiment, the disclosure includes the compounds of formula (II)wherein R⁵ is CH₃, F, or Cl.

In one embodiment, the disclosure includes the compounds of formula (II)wherein Ar is phenyl. In a further aspect, Ar is phenyl and the L groupis positioned para to the core imidazopyridine/pyrazine.

In one embodiment, the disclosure includes the compounds of formula (II)wherein Ar is phenyl, the group L is arranged para to the depicted coreimidazopyridine/pyrazine, and Ar is either unsubstituted or substitutedat one or more of the 2 and 3 positions.

In one embodiment, the disclosure includes the compounds of formula (II)wherein L is —CH₂CH₂—.

In one embodiment, the disclosure includes the compounds of formula (II)wherein n is 0.

In one embodiment, the disclosure includes the compounds of formula (II)wherein n is 1.

One embodiment of the present disclosure is a compound of the presentdisclosure selected from:

-   1-(4-chlorophenyl)sulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;-   1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(o-tolylsulfonyl)urea;-   1-(benzenesulfonyl)-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;-   1-cyclopentylsulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;-   1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-[4-(trifluoromethoxy)phenyl]sulfonyl-urea;-   1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-thienyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(6,8-dichloro-2-ethyl-imidazo[1,2-a]pyridin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(6-cyano-2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)    urea;-   1-[2-[4-(2-ethyl-8-methyl-6-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-[2-ethyl-8-methyl-6-(3-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-[2-ethyl-8-methyl-6-(4-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(6,8-dimethyl-2-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(2-isoxazol-3-yl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(6,8-dimethyl-2-tetrahydrofuran-3-yl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(2-ethyl-6,8-difluoro-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)    urea;-   1-[2-[4-[6,8-dimethyl-2-(1-methylsulfonyl-4-piperidyl)    imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;    or a veterinary, or pharmaceutically acceptable salt thereof.

One embodiment of the disclosure includes compositions comprising acompound of Formula (II) and a pharmaceutically or veterinary acceptablecarrier. The compositions of the disclosure can also be in a variety offorms which include, but are not limited to, oral formulations,injectable formulations, and topical, dermal, or subdermal formulations.The formulations are intended to be administered to an animal, whichincludes, but is not limited to, mammals, and birds. Examples of mammalsinclude, but are not limited to, humans, cattle, sheep, goats, llamas,alpacas, pigs, horses, donkeys, dogs, cats, and other livestock ordomestic mammals. Examples of birds include turkeys, chickens,ostriches, and other livestock or domestic birds.

Another embodiment of the present disclosure includes combinationtherapy, whereby one or more compounds of Formula (II) can be employedas such or in the form of their preparations or formulations ascombinations with one or more other veterinary or pharmaceuticallyactive substances, such as, for example, EP4 antisense nucleic acids,amino acids, peptides, carbohydrates, anti-EP4 antibodies, COX-2selective, COX-1 selective or non-selective NSAIDs, opioids, localanesthetics, disease-modifying, anti-rheumatoid drugs, or steroids. Thecombinations may be part of the same formulation or may be administeredseparately or sequentially to the locus.

Another embodiment of the present disclosure includes a method fortreating pain comprising administration to a subject in need thereof ofan effective amount of a compound of Formula (II) or a compositioncomprising a compound of formula (II).

In one embodiment of the present disclosure, the subject is a mammal.

In another embodiment of the present disclosure, the mammal is acompanion animal.

In another embodiment of the present disclosure, the pain is associatedwith one or more joint pain musculoskeletal pain, lower back pain, neckpain, skeletal pain, sprain, strain, myositis, neuralgia, fibromyalgia,synovitis, arthritis, rheumatoid arthritis, degenerative joint disease,osteoarthritis, gout, ankylosing spondylitis, and bursitis.

Another embodiment of the present disclosure includes the use of acompound of formula (II) for the manufacture of a medicament for use intreating pain.

Another embodiment of the present disclosure includes a compoundcomprising:

-   1-(4-chlorophenyl)sulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;-   1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(o-tolylsulfonyl)urea;-   1-(benzenesulfonyl)-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;-   1-cyclopentylsulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;-   1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-[4-(trifluoromethoxy)phenyl]sulfonyl-urea;-   1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-thienyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(6,8-dichloro-2-ethyl-imidazo[1,2-a]pyridin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(6-cyano-2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)    urea;-   1-[2-[4-(2-ethyl-8-methyl-6-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-[2-ethyl-8-methyl-6-(3-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-[2-ethyl-8-methyl-6-(4-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(6,8-dimethyl-2-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(2-isoxazol-3-yl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(6,8-dimethyl-2-tetrahydrofuran-3-yl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(2-ethyl-6,8-difluoro-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)    urea;-   1-[2-[4-[6,8-dimethyl-2-(1-methylsulfonyl-4-piperidyl)    imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;    or a veterinary, or pharmaceutically acceptable salt thereof.

Another embodiment of the present disclosure includes a compositioncomprising:

-   1-(4-chlorophenyl)sulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;-   1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(o-tolylsulfonyl)urea;-   1-(benzenesulfonyl)-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;-   1-cyclopentylsulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;-   1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-[4-(trifluoromethoxy)phenyl]sulfonyl-urea;-   1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-thienyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(6,8-dichloro-2-ethyl-imidazo[1,2-a]pyridin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(6-cyano-2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)    urea;-   1-[2-[4-(2-ethyl-8-methyl-6-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-[2-ethyl-8-methyl-6-(3-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-[2-ethyl-8-methyl-6-(4-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(6,8-dimethyl-2-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(2-isoxazol-3-yl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(6,8-dimethyl-2-tetrahydrofuran-3-yl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(2-ethyl-6,8-difluoro-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)    urea;-   1-[2-[4-[6,8-dimethyl-2-(1-methylsulfonyl-4-piperidyl)    imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;    and a pharmaceutically or veterinary acceptable carrier.

Another embodiment of the present disclosure includes a combinationcomprising:

-   1-(4-chlorophenyl)sulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;-   1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(o-tolylsulfonyl)urea;-   1-(benzenesulfonyl)-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;-   1-cyclopentylsulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;-   1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-[4-(trifluoromethoxy)phenyl]sulfonyl-urea;-   1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-thienyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(6,8-dichloro-2-ethyl-imidazo[1,2-a]pyridin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(6-cyano-2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)    urea;-   1-[2-[4-(2-ethyl-8-methyl-6-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-[2-ethyl-8-methyl-6-(3-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-[2-ethyl-8-methyl-6-(4-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(6,8-dimethyl-2-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(2-isoxazol-3-yl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(6,8-dimethyl-2-tetrahydrofuran-3-yl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(2-ethyl-6,8-difluoro-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)    urea;-   1-[2-[4-[6,8-dimethyl-2-(1-methylsulfonyl-4-piperidyl)    imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;    and one or more other pharmaceutically or veterinary active    substances.

Another embodiment of the present disclosure includes a method fortreating pain comprising administration to a subject in need thereof aneffective amount of:

-   1-(4-chlorophenyl)sulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;-   1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(o-tolylsulfonyl)urea;-   1-(benzenesulfonyl)-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;-   1-cyclopentylsulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;-   1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-[4-(trifluoromethoxy)phenyl]sulfonyl-urea;-   1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-thienyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(6,8-dichloro-2-ethyl-imidazo[1,2-a]pyridin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(6-cyano-2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)    urea;-   1-[2-[4-(2-ethyl-8-methyl-6-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-[2-ethyl-8-methyl-6-(3-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-[2-ethyl-8-methyl-6-(4-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(6,8-dimethyl-2-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(2-isoxazol-3-yl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(6,8-dimethyl-2-tetrahydrofuran-3-yl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;-   1-[2-[4-(2-ethyl-6,8-difluoro-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)    urea;-   1-[2-[4-[6,8-dimethyl-2-(1-methylsulfonyl-4-piperidyl)    imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;    or a veterinary or pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

One or more aspects and embodiments may be incorporated in a differentembodiment although not specifically described. That is, all aspects andembodiments can be combined in any way or combination.

Definitions

When referring to the compounds disclosed herein, the following termshave the following meanings unless indicated otherwise. The followingdefinitions are meant to clarify, but not limit, the terms defined. If aparticular term used herein is not specifically defined, such termshould not be considered indefinite. Rather, terms are used within theiraccepted meanings.

As used herein, “alkyl” refers to monovalent saturated aliphatichydrocarbyl groups having from 1 to 20 carbon atoms, preferably 1-8carbon atoms, preferably 1-6 carbon atoms.

The hydrocarbon chain can be either straight-chained or branched.Illustrative alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, iso-butyl, and tert-butyl. Similarly, an “alkenyl” group refersto an alkyl group having one or more double bonds present in the chain.

As used herein, “alkoxy” refers to —O-alkyl. Examples of an alkoxy groupinclude methoxy, ethoxy, and n-propoxy.

As used herein, “aryl” refers to a polyunsaturated, aromatic hydrocarbongroup having a single ring (monocyclic) or multiple rings (bicyclic),which can be fused together or linked covalently. Aryl groups with 6-10carbon atoms are preferred, where this number of carbon atoms can bedesignated by C₆₋₁₀, for example. Examples of aryl groups include phenyland naphthalene-1-yl, naphthalene-2-yl, biphenyl, and the like. Arylgroups can be substituted or unsubstituted, unless otherwise indicated.

As used herein, “cycloalkyl” refers to an unsaturated or partiallysaturated hydrocarbon ring, containing from 3 to 7 ring atoms.Illustrative cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, as well as partially saturatedversions thereof, such as cyclohexenyl, and cyclohexadienyl.

As used herein “halogen” or “halo” refers to a halogen. In someembodiments, the halogen is preferably Br, Cl, or F.

As used herein, “haloalkyl” refers to monovalent saturated aliphatichydrocarbyl groups having from 1 to 20 carbon atoms, preferably 1-8carbon atoms, preferably 1-6 carbon atoms, wherein at least one hydrogenatom is substituted by a halogen, including but not limited to perhalogroups where all hydrogen atoms are replaced with halogen atoms. Thehaloalkyl chain can be either straight-chained or branched. Illustrativealkyl groups include trifluoromethyl, trichloromethyl, trifluoroethyl,trifluoropropyl, trifluorobutyl, and pentafluoroethyl. Similarly, a“haloalkenyl” group refers to a haloalkyl group having one or moredouble bonds present in the chain.

As used herein, “heterocyclyl” refers to a saturated or unsaturatednon-aromatic ring containing at least one heteroatom (typically 1 to 5heteroatoms) selected from nitrogen, oxygen or sulfur. The heterocyclylring may be monocyclic or bicyclic. Preferably, these groups contain 0-5nitrogen atoms, 0-2 sulfur atoms and 0-2 oxygen atoms. More preferably,these groups contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygenatoms. Examples of heterocycle groups include pyrrolidine, piperidine,imidazolidine, pyrazolidine, butyrolactam, valerolactam,imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine,1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide,thiomorpholine-S,S-dioxide, piperazine, pyran, pyridone, 3-pyrroline,thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidineand the like. Preferred heterocyclic groups are monocyclic, though theymay be fused or linked covalently to an aryl or heteroaryl ring system.

As used herein “heteroaryl” refers to an aromatic group containing atleast one heteroatom, where the heteroaryl group may be monocyclic orbicyclic. Examples include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl,triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl,phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl,benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl,benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl,imidazopyridines, benzothiazolyl, benzofuranyl, benzothienyl, indolyl,azaindolyl, azaindazolyl, quinolyl, isoquinolyl, isothiazolyl,pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl,furyl or thienyl. Preferred heteroaryl groups are those having at leastone aryl ring nitrogen atom, such as quinolinyl, quinoxalinyl, purinyl,benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzothiazolyl, indolyl,quinolyl, isoquinolyl and the like. Preferred 6-ring heteroaryl systemsinclude pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl and thelike. Preferred 5-ring heteroaryl systems include isothiazolyl,pyrazolyl, imidazolyl, thienyl, furyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl and the like.

As used herein “optionally substituted” refers to a substitution of ahydrogen atom, which would otherwise be present on the substituent. Whendiscussing ring systems, the optional substitution is typically with 1,2, or 3 substituents replacing the normally-present hydrogen. Whenreferencing straight and branched moieties, however, the number ofsubstitutions can be more, occurring wherever hydrogen is usuallypresent. The substitutions can be the same or different. Illustrativesubstitutions include nitro, NR′R″, cyano, —NR′COR′″, alkyl, alkenyl,C(O), SO₂R′″, NR′SO₂R′″, SO₂NR′R″, CONR′R″, CONHC₆H₅, hydroxy, alkoxy,alkylsulfonyl, haloalkyl, haloalkenyl, haloalkoxy, mercapto (SH),thioalkyl, halogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl, aseach is understood in the art, and where R′ and R″ are the same ordifferent and each represents hydrogen or alkyl; or when R′ and R″ areeach attached to a nitrogen atom, they may form a saturated orunsaturated heterocyclic ring containing from 4 to 6 ring atoms, andwherein R′″ is alkyl or haloalkyl.

As used herein the phrase veterinary or veterinarily or pharmaceuticalor pharmaceutically acceptable salt refers to any salt of a compounddisclosed herein which retains its biological properties and which isnot toxic or otherwise undesirable for veterinary or pharmaceutical use.Certain compounds of the present disclosure have sites that would allowfor a veterinary or veterinarily, or pharmaceutical or pharmaceuticallyacceptable salt, and such salt forms are also included in the presentdisclosure. Such salts may be derived from a variety of organic andinorganic counter-ions known in the art. Such salts include: (1) acidaddition salts formed with organic or inorganic acids such ashydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic,acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic,cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic,succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric,benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic,phthalic, lauric, methanesulfonic, ethanesulfonic,1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic,4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic,camphoric, camphorsulfonic,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic, glucoheptonic,3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric,gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic,cyclohexylsulfamic, quinic, muconic acid, and like acids.

Salts further include, by way of example only, salts of non-toxicorganic or inorganic acids, such as halides, such as, chloride andbromide, sulfate, phosphate, sulfamate, nitrate, acetate,trifluoroacetate, trichloroacetate, propionate, hexanoate,cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate,malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate,tartarate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate,cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate),ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate,benzenesulfonate (besylate), 4-chlorobenzenesulfonate,2-naphthalenesulfonate, 4-toluenesulfonate, camphorate,camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate,glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate,lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate,salicylate, stearate, cyclohexylsulfamate, quinate, muconate, and thelike.

Examples of inorganic bases that can be used to form base addition saltsinclude, but are not limited to, metal hydroxides, such as lithiumhydroxide, sodium hydroxide, and potassium hydroxide; metal amides, suchas lithium amide and sodium amide; metal carbonates, such as lithiumcarbonate, sodium carbonate, and potassium carbonate; and ammonium basessuch as ammonium hydroxide and ammonium carbonate.

Examples of organic bases that can be used to form base addition saltsinclude, but are not limited to, metal alkoxides, such as lithium,sodium, and potassium alkoxides including lithium methoxide, sodiummethoxide, potassium methoxide, lithium ethoxide, sodium ethoxide,potassium ethoxide, and potassium tert-butoxide; quaternary ammoniumhydroxides, such as choline hydroxide; and amines including, but notlimited to, aliphatic amines (i.e., alkylamines, alkenylamines,alkynylamines, and alicyclic amines), heterocyclic amines, arylamines,heteroarylamines, basic amino acids, amino sugars, and polyamines.

According to embodiments of the present disclosure, the base can be aquaternary ammonium hydroxide, wherein one or more of the alkyl groupsof the quaternary ammonium ion are optionally substituted with one ormore suitable substituents. Preferably, at least one alkyl group issubstituted with one or more hydroxyl groups. Non-limiting examples ofquaternary ammonium hydroxides that can be used in accordance with thepresent disclosure include choline hydroxide, trimethylethylammoniumhydroxide, tetramethylammonium hydroxide, and is preferably cholinehydroxide. According to embodiments of the present disclosure, analkylamine base can be substituted or unsubstituted. Non-limitingexamples of unsubstituted alkylamine bases that can be used inaccordance with the present disclosure include methylamine, ethylamine,diethylamine, and triethylamine. A substituted alkylamine base ispreferably substituted with one or more hydroxyl groups, and preferablyone to three hydroxyl groups. Non-limiting examples of substitutedalkylamine bases that can be used in accordance with the presentdisclosure include 2-(diethylamino)ethanol, N,N-dimethylethanolamine(deanol), tromethanine, ethanolamine, and diolamine.

As used herein, the terms “subject” and “patient” are usedinterchangeably herein. The terms “subject” and “subjects” refer to aprimate such as a monkey such as a cynomolgus monkey, a chimpanzee, anda human or non-primate animal. In one embodiment, the subject is ahuman. In another embodiment, the subject is a companion animal such asa dog or cat. In a further embodiment, the subject is an animal ofagricultural importance such as a sheep, cow, horse, goat, fish, pig, ordomestic fowl (such as a chicken, turkey, duck, or goose).

In addition, certain compounds of the present disclosure havesubstituent groups that would allow for a pharmaceutically acceptableprodrug moiety, and such prodrug forms are also included in the presentdisclosure. A pharmaceutically acceptable prodrug refers to a compoundhaving a group which may be converted into an amino group, a hydroxylgroup, a carboxyl group, or the like, by solvolysis or under aphysiological condition. Examples of the groups forming the prodruginclude those as described in Prog. Med., 5, 2157-2161 (1985) or“Pharmaceutical Research and Development” (Hirokawa Publishing Company,1990), vol. 7, Drug Design, 163-198. The term prodrug is used throughoutthe specification to describe any pharmaceutically acceptable form of acompound, which upon administration to a patient, provides the activecompound. Pharmaceutically acceptable prodrugs refer to a compound thatis metabolized, for example hydrolyzed or oxidized, in the host to formthe compound of the present disclosure. Typical examples of prodrugsinclude compounds that have biologically labile protecting groups on afunctional moiety of the active compound. Prodrugs include compoundsthat may be oxidized, reduced, aminated, deaminated, hydroxylated,dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated,acylated, deacylated, phosphorylated, dephosphorylated to produce theactive compound.

The present disclosure includes all pharmaceutically acceptableisotopically-labelled compounds of the disclosure wherein one or moreatoms are replaced by atoms having the same atomic number, but an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes suitable for inclusion inthe compounds of the disclosure include isotopes of hydrogen, such as ²Hand ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl,fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P,and sulfur, such as ³⁵S. Certain isotopically-labelled compounds of thedisclosure, such as those incorporating a radioactive isotope, may beuseful in drug or substrate tissue distribution studies. The radioactiveisotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularlyuseful for this purpose in view of their ease of incorporation and readymeans of detection. Substitution with heavier isotopes such asdeuterium, i.e. ²H, may afford certain therapeutic advantages resultingfrom greater metabolic stability, for example, increased in vivohalf-life or reduced dosage requirements, and hence may be preferred insome circumstances. Substitution with positron emitting isotopes, suchas ¹¹C, ¹⁸F, ¹⁵O and ¹³N, may be useful in Positron Emission Topography(PET) studies for examining substrate receptor occupancy.Isotopically-labelled compounds of the disclosure may generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described in the accompanying Examplesand Preparations using an appropriate isotopically-labelled reagents inplace of the non-labelled reagent previously employed.

In certain cases, the depicted substituents can contribute to opticaland/or stereoisomerism. Compounds having the same molecular formula butdiffering in the nature or sequence of bonding of their atoms or in thearrangement of their atoms in space are termed “isomers.” Isomers thatdiffer in the arrangement of their atoms in space are termed“stereoisomers.” Stereoisomers that are not mirror images of one anotherare termed “diastereomers” and those that are non-superimposable mirrorimages of each other are termed “enantiomers”. When a compound has anasymmetric center, for example when it is bonded to four differentgroups, a pair of enantiomers is possible. An enantiomer can becharacterized by the absolute configuration of its asymmetric center andis designated (R) or (S) according to the rules of Cahn and Prelog (Cahnet al., 1966, Angew. Chem. 78: 413-447, Angew. Chem., Int. Ed. Engl. 5:385-414 (errata: Angew. Chem., Int. Ed. Engl. 5:511); Prelog andHelmchen, 1982, Angew. Chem. 94: 614-631, Angew. Chem. Internat. Ed.Eng. 21: 567-583; Mata and Lobo, 1993, Tetrahedron: Asymmetry 4:657-668) or can be characterized by the manner in which the moleculerotates the plane of polarized light and is designated dextrorotatory orlevorotatory (namely, as (+)- or (−)-isomers, respectively). A chiralcompound can exist as either an individual enantiomer or as a mixturethereof. A mixture containing equal proportions of enantiomers is calleda “racemic mixture”.

In certain embodiments, the compounds disclosed herein can possess oneor more asymmetric centers; and such compounds can therefore be producedas the individual (R)- or (S)-enantiomer or as a mixture thereof. Unlessindicated otherwise, for example by designation of stereochemistry atany position of a formula, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof.Methods for determination of stereochemistry and separation ofstereoisomers are well-known in the art.

In certain embodiments, the compounds disclosed herein are“stereochemically pure”. A stereochemically pure compound has a level ofstereochemical purity that would be recognized as “pure” by those ofskill in the art. Of course, this level of purity may be less than 100%.In certain embodiments, “stereochemically pure” designates a compoundthat is substantially free, i.e. at least about 85% or more, ofalternate isomers. In particular embodiments, the compound is at leastabout 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or about99.9% free of other isomers.

Synthesis

Generally the compounds of the disclosure can be prepared, isolated orobtained by any method apparent to those of skill in the art. Exemplarymethods of preparation are illustrated by the following schemes:

Alternatively, compounds of the present disclosure can be formedaccording to the below scheme, involving palladium coupling a fullyelaborated boronic acid derivative, rather than generating a Bocprotected intermediate:

Alternatively, compounds of the present disclosure can be formedaccording to the below scheme, involving the formation of theimidazopyridine or imidazopyrazine ring with the Ar-L-N alreadyinstalled, then further elaboration to the desired compounds:

Compositions and Methods of Administration

The compounds of formula (II) used in the methods disclosed herein canbe administered in certain embodiments using veterinary orpharmaceutical compositions including at least one compound of formula(II), if appropriate in the salt form, either used alone or in the formof a combination with one or more compatible and veterinary orpharmaceutically acceptable carriers, such as diluents or adjuvants, orwith another agent. There are provided compositions which comprise aderivative of formula (II) or a salt thereof, and an acceptableexcipient, carrier or diluent. The composition can also be in a varietyof forms which include, but are not limited to, oral formulations,injectable formulations, and topical, dermal or subdermal formulations.

The composition can be in a form suitable for oral use, for example, asdietary supplements, troches, lozenges, chewables, tablets, hard or softcapsules, emulsions, aqueous or oily suspensions, aqueous or oilysolutions, dispersible powders or granules, syrups, or elixirs.Compositions intended for oral use can be prepared according to anymethod known in the art for the manufacture of veterinary orpharmaceutical compositions and such compositions can contain one ormore agents selected from the group consisting of sweetening agents,bittering agents, flavoring agents, coloring agents and preservingagents in order to provide elegant and palatable preparations.

Lozenges are solid compositions containing one or more activeingredients intended to dissolve or disintegrate slowly in the oralcavity by passive incubation in the oral cavity, or actively by suckingor chewing. They can be used for systemic effect if the drug is absorbedthrough the buccal or esophageal lining or is swallowed. In particular,soft lozenges can be chewed or allowed to dissolve slowly in the mouth.These dosage forms have the advantage of being flavored and thus easy toadminister to both human and animal patients; have formulas that areeasy to change and can be patient specific; can deliver accurate amountsof the active ingredient to the oral cavity and digestive system; andallow for the drug to remain in contact with the oral or esophagealcavity for an extended period of time.

Tablets can contain the active ingredient in admixture with non-toxic,pharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients can be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc. The tablets may be uncoated orthey may be coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period.

Formulations for oral use can be hard gelatin capsules, wherein theactive ingredient is mixed with an inert solid diluent, for example,calcium carbonate, calcium phosphate or kaolin. Capsules can also besoft gelatin capsules, wherein the active ingredient is mixed with wateror miscible solvents such as propylene glycol, PEGs and ethanol, or anoil medium, for example, peanut oil, liquid paraffin, or olive oil.

The compositions can also be in the form of oil-in-water or water-in-oilemulsions. The oily phase can be a vegetable oil, for example, olive oilor arachis oil, or a mineral oil, for example, liquid paraffin ormixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example, soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example, sorbitan monoleate, and condensation productsof the said partial esters with ethylene oxide, for example,polyoxyethylene sorbitan monooleate. The emulsions can also containsweetening agents, bittering agents, flavoring agents, andpreservatives.

In one embodiment of the formulation, the composition is in the form ofa microemulsion. Microemulsions are well suited as the liquid carriervehicle. Microemulsions are quaternary systems comprising an aqueousphase, an oily phase, a surfactant and a cosurfactant. They aretranslucent and isotropic liquids. Microemulsions are composed of stabledispersions of microdroplets of the aqueous phase in the oily phase orconversely of microdroplets of the oily phase in the aqueous phase. Thesize of these microdroplets is less than 200 nm (1000 to 100,000 nm foremulsions). The interfacial film is composed of an alternation ofsurface-active (SA) and co-surface-active (Co-SA) molecules which, bylowering the interfacial tension, allows the microemulsion to be formedspontaneously. In one embodiment of the oily phase, the oily phase canbe formed from mineral or vegetable oils, from unsaturatedpolyglycosylated glycerides or from triglycerides, or alternatively frommixtures of such compounds. In one embodiment of the oily phase, theoily phase comprises of triglycerides; in another embodiment of the oilyphase, the triglycerides are medium-chain triglycerides, for example,C₈-C₁₀ caprylic/capric triglyceride. In another embodiment, the oilyphase will represent a % v/v range selected from the group consisting ofabout 2 to about 15%; about 7 to about 10%; and about 8 to about 9% v/vof the microemulsion. The aqueous phase includes, for example, water orglycol derivatives, such as propylene glycol, glycol ethers,polyethylene glycols or glycerol. In one embodiment of the glycolderivatives, the glycol is selected from the group consisting ofpropylene glycol, diethylene glycol monoethyl ether, dipropylene glycolmonoethyl ether and mixtures thereof. Generally, the aqueous phase willrepresent a proportion from about 1 to about 4% v/v in themicroemulsion. Surfactants for the microemulsion include diethyleneglycol monoethyl ether, dipropylene glycol monomethyl ether,polyglycolyzed C₈-C₁₀ glycerides or polyglyceryl-6 dioleate. In additionto these surfactants, the cosurfactants include short-chain alcohols,such as ethanol and propanol. Some compounds are common to the threecomponents discussed above, for example, aqueous phase, surfactant andcosurfactant. However, it is well within the skill level of thepractitioner to use different compounds for each component of the sameformulation. In one embodiment for the amount ofsurfactant/cosurfactant, the cosurfactant to surfactant ratio will befrom about 1/7 to about 1/2.

In another embodiment for the amount of cosurfactant, there will be fromabout 25 to about 75% v/v of surfactant and from about 10 to about 55%v/v of cosurfactant in the microemulsion.

Oily suspensions can be formulated by suspending the active ingredientin a vegetable oil, for example, atachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions can contain a thickening agent, for example, beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as sucrose, saccharinor aspartame, bittering agents, and flavoring agents can be added toprovide a palatable oral preparation. These compositions can bepreserved by the addition of an anti-oxidant such as ascorbic acid, orother known preservatives.

Aqueous suspensions can contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents can be a naturally-occuring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example, polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide, with partial esters derived from fatty acidsand hexitol anhydrides, for example, polyethylene sorbitan monooleate.The aqueous suspensions can also contain one or more preservatives, forexample, ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agentsand/or bittering agents, such as those set forth above.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, bittering, flavoring andcoloring agents, can also be present.

Syrups and elixirs can be formulated with sweetening agents, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative, flavoringagent(s) and coloring agent(s).

The compositions can be in the form of a sterile injectable aqueous oroleagenous suspension. This suspension can be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation can also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example, as a solution in 1,3-butane diol. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solutionand isotonic sodium chloride solution. Cosolvents such as ethanol,propylene glycol or polyethylene glycols can also be used.Preservatives, such as phenol or benzyl alcohol, can be used.

In addition, sterile, fixed oils are conventionally employed as asolvent or suspending medium. For this purpose, any bland fixed oil canbe employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

Topical, dermal and subdermal formulations can include emulsions,creams, ointments, gels or pastes, or spot-on formulations.

Organic solvents that can be used in the disclosure include but are notlimited to: acetyltributyl citrate, fatty acid esters such as thedimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzylalcohol, butyl diglycol, dimethylacetamide, dimethylformamide,dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol,ethylene glycol monoethyl ether, ethylene glycol monomethyl ether,monomethylacetamide, dipropylene glycol monomethyl ether, liquidpolyoxyethylene glycols, propylene glycol, 2-pyrrolidone (e.g.N-methylpyrrolidone), diethylene glycol monoethyl ether, ethylene glycoland diethyl phthalate, or a mixture of at least two of these solvents.

As vehicle or diluent, compositions of the present disclosure mayinclude plant oils such as, but not limited to soybean oil, groundnutoil, castor oil, corn oil, cotton oil, olive oil, grape seed oil,sunflower oil, etc.; mineral oils such as, but not limited to,petrolatum, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbonsor alternatively, for example, medium-chain (such as C₈-C₁₂)triglycerides.

Dosage forms can contain from about 0.5 mg to about 5 g of an activeagent.

In one embodiment of the disclosure, the active agent is present in theformulation at a concentration of about 0.05 to 10% weight/volume.

The compounds of formula (II) can be employed as such or in the form oftheir preparations or formulations as combinations

The compounds of formula (II) according to the disclosure may becombined with one or more agents having the same sphere of activity, forexample, to increase activity, or with substances having another sphereof activity, for example, to broaden the range of activity. Thecompounds of formula (II) have been found to possess activity asprostaglandin E2 receptor antagonist, preferably as EP4 receptorantagonists. Thus, the compounds of the present disclosure may also becombined with other agents that inhibit EP4 activity. Such EP4inhibitors can include small molecules, nucleic acids, e.g., EP4antisense nucleic acids, amino acids, peptides, carbohydrates, andanti-EP4 antibodies. Preferably, such agents are combined with apharmaceutically acceptable delivery vehicle or carrier. Examples of EP4antibodies include, for example, polyclonal, monoclonal, humanized,anti-idiotypic, chimeric or single chain antibodies, Fab, F(ab′)₂, andFab expression library fragments, scFV molecules, and epitope-bindingfragments thereof. An antisense oligonucleotide directed to the EP4 geneor mRNA to inihibt its expression is made according to standardtechniques (see, e.g., Agrawal et al., Methods in Molecular Biology:Protocols for Oligonucleotides and Analogs, Vol. 20, (1993)).

For anti-EP4 antibodies, the preferred dosage is generally 0.2 mg/kg to20 mg/kg body weight. Generally, partially humanized antibodies andfully human antibodies have a longer half-life within the human bodythan other antibodies. Accordingly, lower dosages and less frequentadministration are possible. Modifications such as lipidation can beused to stabilize antibodies and to enhance uptake and tissuepenetration. A method for lipidation of antibodies is described inCruikshank et al., J. Acquired Immune Deficiency Syndromes Hum.Retrovirol. 14: 193, (1997).

The compounds of formula (II) may also be co-administered with a COX-2selective NSAID. Further, the present disclosure also encompasses apharmaceutical composition for the treatment of inflammation, rheumatoidarthritis, pain, common cold, osteoarthritis, neuropathic pain, braintumor, diuresis, or the like, which comprises a therapeuticallyeffective amount the aryl or heteroaryl fused imidazole compound offormula (II) and a COX-2 selective NSAID or their veterinary orpharmaceutically acceptable salt together with a veterinary orpharmaceutically acceptable carrier.

The compounds of the disclosure may advantageously be employed incombination with one or more other therapeutic ingredients selected froma COX-2 selective NSAID, COX-1 selective NSAID, non-selective NSAIDs,opioids, anticonvulsants, antidepressants, local anesthetics,disease-modifying anti-rheumatoid drugs, or steroids.

The combination with a COX-2 selective NSAID is particularly favored foruse in the prophylaxis and treatment of pain and arthritis. Examples ofa COX-2 selective NSAID are nimesulide, celecoxib, rofecoxib, firocoxiband valdecoxib.

The pharmaceutical preparation comprising the compounds of formula (II),for delivery to a human or other mammal, is preferably in unit dosageform, in which the preparation is subdivided into unit doses containingan appropriate quantity of the active component. The unit dosage formcan be a packaged preparation containing discrete quantities of thepreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet or lozengeitself, or it can be an appropriate number of any of these in packagedform.

The quantity of active component in a unit dose preparation can bevaried or adjusted from about 0.1 mg to about 1000 mg, according to theparticular application and the potency of the active component. Thecomposition can, if desired, also contain other compatible therapeuticagents.

In therapeutic use for the treatment or prevention of pain orinflammation in a human or other mammal, the compounds utilized in themethod of treatment are administered at an initial dosage of about 0.1mg/kg to about 100 mg/kg per interval. Preferred intervals may be daily,weekly, monthly, quarterly, semi-annually, or annually. The dosages canbe varied depending on the requirements of the patient, for example, thesize of the human or mammal being treated, the severity of the conditionbeing treated, the route of administration, and the potency of thecompound(s) being used. Determination of the proper dosage and route ofadministration for a particular situation is within the skill of thepractitioner. Generally, the treatment will be initiated with smallerdosages, which are less than the optimum dose of the compound, which canbe increased in small increments until the optimum effect under theparticular circumstances of the infection is reached. For convenience,the total daily dosage can be divided and administered in portionsduring the day if desired.

In therapeutic use, the compounds of formula (II) are useful inmanufacture of a medicament for a method of the treating of painassociated with rheumatic fever, influenza or other viral infections,common cold, lower back and neck pain, skeletal pain, postpartum pain,dysmenorrhea, headache, migraine, toothache, sprains and strains,myositis, neuralgia, fibromyalgia, synovitis, arthritis, includingrheumatoid arthritis, degenerative joint disease (osteoarthritis), goutand ankylosing spondylitis, bursitis, burns including radiation andcorrosive chemical injuries, sunburns, pain following surgical anddental procedures or bone fracture, immune and autoimmune diseases suchas systemic lupus erythematosus; AIDS (acquired immune deficiencysyndrome), gastrointestinal cancers such as colon cancer; cellularneoplastic transformations or metastatic tumor growth; diabeticretinopathy, tumor angiogenesis, prostanoid-induced smooth musclecontraction associated with dysmenorrhea, premature labor, allergicrhinitis, atopic dermatitis, asthma or eosinophil related disorders,hyperimmunoglobulinaemia, Castleman's disease, myeloma; Alzheimer'sdisease, sleep disorders, endocrine disturbance, glaucoma, bone loss;osteoporosis; promotion of bone formation, Paget's disease;cyto-protection in peptic ulcers, gastritis, regional enteritis,ulcerative colitis, diverticulitis or other gastrointestinal lesions; GIbleeding and patients undergoing chemotherapy; coagulation disordersselected from hypoprothrombinemia, hemophilia and other bleedingproblems; kidney disease; thrombosis; occlusive vascular disease;pre-surgery; and anti-coagulation, or the like in mammals, especiallyhumans, dogs and cats.

The compounds of the present disclosure are intended for use in themanagement of pain of any origin. Psychological factors play a key rolein both onset and progress of any pain disorder. In pain disorders, painis perceived in different anatomic locations such as lower back, headregion, abdomen, joints, and chest. Abnormal signal transmission andprocessing in the nervous system are a legitimate explanation for thiscondition. Although evidence suggests that pain disorder is widelyprevalent in the general population, research still fails to addressnumerous aspects of pain diagnosis and management. For example,diagnostic criteria for human pain differ in various Diagnostic andStatistical Manual of Mental Disorders (DSM) such as DSM-III, DSM-IIIrevised, DSM-IV, and DSM-IV-textual revisions; hence, a morecomprehensive classification is needed. Pain management in animal healthis yet more complex. The ability to understand and investigate thepathophysiologic process underlying a disorder depends on a valid,reliable classification system and common terminology to make effectivecommunication among the academicians, clinicians, researchers, andsubjects. The compounds of the present disclosure are intended for usein pain management for any such pain classification criteria useful inany subject.

The compounds of formula (II) may, in particular, be used in the fieldsof veterinary medicine, livestock husbandry and in particular,warm-blooded vertebrates, including companion animals such as dogs andcats, horses, livestock, and fowl.

The compounds of the present disclosure, stereoisomers thereof, andveterinary or pharmaceutically acceptable salts thereof, andcompositions comprising compounds of the present disclosure inconjunction with at least one other veterinary agent are of particularvalue in the control of pain and inflammation in companion animals,particularly dogs and cats, livestock and birds.

Any of the compounds of the present disclosure, or a suitablecombination of a compound of the present disclosure and optionally, withat least one additional veterinary agent may be administered directly tothe animal and/or indirectly by applying it to the local environment inwhich the animal dwells (such as bedding, enclosures, and the like).Direct administration includes contacting the skin, fur, or feathers ofa subject animal with the compound(s), or by feeding or injecting thecompounds into the animal.

The Formula (II) compounds, stereoisomers thereof, and veterinaryacceptable salts thereof, and combinations with at least one additionalveterinary agent, as described herein, are believed to be of value forthe treatment and control of the various symptoms associated witharthritis, including pain and inflammation.

The present disclosure also relates to a method of administering acompound of the present disclosure alone or in combination with at leastone additional veterinary agent, and optionally a veterinary acceptableexcipient, diluent, or carrier, to animals in good health comprising theapplication to said animal to reduce or eliminate the pain andinflammation due to various forms of arthritis.

The present disclosure explicitly encompasses those compounds presentedin Table 1.

A composition comprising a therapeutically acceptable amount of any ofthese compounds is also within the scope of the disclosure. Thecomposition can further comprise a veterinary acceptable excipient,diluent, carrier, or mixture thereof. Such a composition can beadministered to an animal in need thereof to treat and/or prevent aparasitic infection or infestation. The composition can further comprisean additional veterinary agent, as described herein.

TABLE 1 Ref. No. Compound Name 11-(4-chlorophenyl)sulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea 21-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(o-tolylsulfonyl)urea 31-(benzenesulfonyl)-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea 41-cyclopentylsulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea 51-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-[4-(trifluoromethoxy)phenyl]sulfonyl-urea 61-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]ethyl]-3-(p-tolylsulfonyl)urea 71-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-thienyl]ethyl]-3-(p-tolylsulfonyl)urea 81-[2-[4-(6,8-dichloro-2-ethyl-imidazo[1,2-a]pyridin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea 91-[2-[4-(6-cyano-2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea 101-[2-[4-(2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea 111-[2-[4-(2-ethyl-8-methyl-6-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea 121-[2-[4-[2-ethyl-8-methyl-6-(3-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea 131-[2-[4-[2-ethyl-8-methyl-6-(4-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea 141-[2-[4-(6,8-dimethyl-2-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea 151-[2-[4-(2-isoxazol-3-yl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea 161-[2-[4-(6,8-dimethyl-2-tetrahydrofuran-3-yl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea 171-[2-[4-(2-ethyl-6,8-difluoro-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea 181-[2-[4-[6,8-dimethyl-2-(1-methylsulfonyl-4-piperidyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea

Experimental Procedures

Synthesis

The following Examples illustrate the synthesis of representativecompounds of Formula (II). These examples are not intended, nor are theyto be construed, as limiting the scope of the embodiments disclosedherein. It will be clear that various embodiments may be practicedotherwise than as particularly described herein. Numerous modificationsand variations are possible in view of the teachings herein and,therefore, are within the scope of the present disclosure.

Liquid chromatography-mass spectrometry (LCMS) experiments to determineretention times and associated mass ions were performed using one ormore of the following Methods A, B, and C:

Method A:

Waters BEH C18, 3.0×30 mm, 1.7 μm, was used at a temperature of 50° C.and at a flow rate of 1.5 mL/min, 2 μL injection, mobile phase: (A)water with 0.1% formic acid and 1% acetonitrile, mobile phase (B) MeOHwith 0.1% formic acid; retention time given in minutes.

Method A details: (I) ran on a Binary Pump G1312B with UV/Vis diodearray detector G1315C and Agilent 6130 mass spectrometer in positive andnegative ion electrospray mode with UV PDA detection with a gradient of15-95% (B) in a 2.2 min linear gradient (II) hold for 0.8 min at 95% (B)(III) decrease from 95-15% (B) in a 0.1 min linear gradient (IV) holdfor 0.29 min at 15% (B);

Method B:

An Agilent Zorbax Bonus RP, 2.1×50 mm, 3.5 μm, was used at a temperatureof 50° C. and at a flow rate of 0.8 mL/min, 2 μL injection, mobilephase: (A) water with 0.1% formic acid and 1% acetonitrile, mobile phase(B) MeOH with 0.1% formic acid; retention time given in minutes.

Method B details: (I) ran on a Binary Pump G1312B with UV/Vis diodearray detector G1315C and Agilent 6130 mass spectrometer in positive andnegative ion electrospray mode with UV-detection at 220 and 254 nm witha gradient of 5-95% (B) in a 2.5 min linear gradient (II) hold for 0.5min at 95% (B) (III) decrease from 95-5% (B) in a 0.1 min lineargradient (IV) hold for 0.29 min at 5% (B).

Method C:

An API 150EX mass spectrometer linked to a Shimadzu LC-10AT LC systemwith a diode array detector was used. The spectrometer had anelectrospray source operating in positive and negative ion mode. LC wascarried out using an Agilent ZORBAX XDB 50×2.1 mm C18 column and a 0.5mL/minute flow rate. Solvent A: 95% water, 5% acetonitrile containing0.01% formic acid; Solvent B: acetonitrile. The gradient was shown asbelow. 0-0.5 min: 2% solvent (B); 0.5-2.5 min: 2% solvent B to 95%solvent (B); 2.5-4.0 min: 95% solvent (B); 4.0-4.2 min: 95% solvent (B)to 2% solvent B; 4.2-6.0 min: 2% solvent (B).

EXAMPLES

The following Examples provide a more detailed description of theprocess conditions for preparing compounds of the present disclosure. Itis to be understood, however, that the disclosure, as fully describedherein and as recited in the claims, is not intended to be limited bythe details of the following schemes or modes of preparation.

Synthesis of Key Intermediate, tert-butylN-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamate

Intermediate 1: tert-butyl N-[2-(4-bromophenyl)ethyl]carbamate

Dissolved 2-(4-bromophenyl)ethanamine (25.0 g, 124.95 mmol) in DCM (500mL). Charged with di-tert-butyl dicarbonate (32.7 g, 149.94 mmol) andtriethylamine (52 mL, 373.08 mmol). Stirred at room temperature for 16hours. Removed solvent and used crude without further purification.

Intermediate 2: tert-butylN-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamate

Dissolved tert-butyl N-[2-(4-bromophenyl)ethyl]carbamate (˜124.95 mmol)in THF (500 mL). Added bis(pinacolato)diboron (44.0 g, 174.93 mmol),palladium chloride diphenyl phosphine ferrocene (10.2 g, 10 mol %) andpotassium acetate (36.8 g, 374.85 mmol). Heated to 65° C. for 16 hours.Removed solvent and purified using normal phase chromatography (0-100%EtOAc in heptanes) to yield 40.58 g of product; ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.35 (s, 12H) 1.44 (s, 9H) 2.82 (t, J=6.74 Hz, 2H)3.38 (d, J=5.86 Hz, 2H) 4.18-4.71 (m, 1H) 7.21 (d, J=7.42 Hz, 2H) 7.76(d, J=7.61 Hz, 2H).

Example 1 Compound 1.1-(4-chlorophenyl)sulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea

Intermediate 1: 2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazine

Dissolved 3,5-dimethylpyrazin-2-amine (10.0 g, 81.7 mmol) in EtOH (500mL). To this solution added 1-bromo-2-butanone (12.4 mL, 122 mmol).Heated to 65° C. for 16 hours. Removed the solvent in vacuo. Brought upresidue in H₂O (500 mL) and extracted with EtOAc (3×500 mL). Washed thecombined organics with brine and dried over Na₂SO₄. Filtered and removedsolvent. Purified using normal phase chromatography (0-10% MeOH in DCM)to yield 8.7 g (49.5 mmol, 60%) of product; ¹H NMR (400 MHz,CHLOROFORM-d) θ=7.70 (s, 1H), 7.33 (s, 1H), 2.95-2.76 (m, 5H), 2.50-2.40(m, 3H), 1.34 (t, J=7.6 Hz, 3H); LCMS (M/Z): 176.2 (M+H).

Intermediate 2: 3-bromo-2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazine

Dissolved 2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazine (15.1 g, 86.3mmol) in acetic acid (500 mL). Slowly added bromine (4.4 mL, 86.3 mmol)to the solution and stirred at room temperature for two hours.Concentrated via vacuum and diluted with H₂O (400 mL). Adjusted pH to ˜8using NaHCO₃ (saturated aq). Extracted with EtOAc (3×500 mL) andpurified using normal phase chromatography (0-10% MeOH in DCM) to yield12.9 g (59%) of product; ¹H NMR (400 MHz, METHANOL-d₄) θ=8.01 (s, 1H),2.86 (q, J=7.6 Hz, 2H), 2.81 (s, 3H), 2.52 (s, 3H), 1.34 (t, J=7.6 Hz,3H); LCMS (M/Z): 254.0 (M+H).

Intermediate 3: tert-butylN-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]carbamate

Dissolved 3-bromo-2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazine (12.6 g,50.6 mmol) and tert-butylN-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamate(21.1 g, 60.7 mmol) in 1,4-Dioxane (250 mL). Charged with palladiumchloride diphenyl phosphine ferrocene (4.1 g, 10 mol %) and cesiumcarbonate (49.4 g, 151.6 mmol). Heated to 70° C. for 16 hours. Filteredthrough a silica plug and rinsed with 0-10% MeOH in DCM to yield 15.2grams (38.6 mmol) of semi-crude product; LCMS (M/Z): 395.2 (M+H).

Intermediate 4:2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethanamine

Dissolved tert-butylN-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]carbamate(15.2 g, 38.6 mmol) in DCM (300 mL) and cooled to 0° C. Slowly addedtrifluoracetic acid (30 mL, 390 mmol) to the solution. Allowed to warmto room temperature and stir for 16 hours. Neutralized to pH-8 usingNaHCO₃(saturated). Collected organic. Washed the organic with brine anddried over Na₂SO₄. Filtered and removed solvent and purified usingnormal phase chromatography (0-10% MeOH in DCM) to yield 12.9 g (59%) ofproduct; ¹H NMR (400 MHz, METHANOL-d₄) δ=7.82 (s, 1H), 7.61-7.43 (m,4H), 3.19 (q, J=7.3 Hz, 2H), 3.12-3.00 (m, 2H), 2.88-2.71 (m, 5H), 2.38(s, 3H), 1.36-1.27 (m, 3H); LCMS (M/Z): 295.2 (M+H).

1-(4-chlorophenyl)sulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea

4-Chlorobenzenesulfonyl isocyanate (25 μL, 0.170 mmol) was added to asolution of2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethanamine(50 mg, 0.170 mmol) and CH₂Cl₂ (1 mL). After 1.5 h volatiles wereremoved, and the resulting residue was purified by silica gel columnchromatography, eluting with a gradient of 0 to 100% EtOAc in heptane.The title compound was obtained as a white solid (60 mg, 69%). ¹H NMR(500 MHz, CHLOROFORM-d): δ ppm 1.33 (t, J=7.6 Hz, 3H), 2.49 (s, 3H),2.88 (q, J=7.5 Hz, 2H), 2.91-2.95 (m, 2H), 3.02 (s, 3H), 3.56 (q, J=6.6Hz, 2H), 6.74 (t, J=5.3 Hz, 1H), 7.35-7.38 (m, 2H), 7.39-7.42 (m, 2H),7.45 (d, J=8.8 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H), 7.82 (s, 1H); m/z 512[M+H]⁺, 510 [M−H]⁻.

Compound 2:1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(o-tolylsulfonyl)urea

2-Tolylsulfonyl isocyanate (26 μL, 0.170 mmol) was added to a solutionof2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethanamine(50 mg, 0.170 mmol) in CH₂Cl₂ (1 mL). After 30 minutes volatiles wereremoved, and the resulting residue was purified by silica gel columnchromatography, eluting with a gradient of 0 to 100% EtOAc in heptane.The title compound was obtained as an off-white solid (63 mg, 75%). ¹HNMR (400 MHz, CHLOROFORM-d): δ ppm 1.34 (t, J=7.5 Hz, 3H), 2.52 (s, 3H),2.60 (s, 3H), 2.84-2.92 (m, 4H), 3.04 (s, 3H), 3.53 (q, J=6.5 Hz, 2H),6.79 (t, J=5.2 Hz, 1H), 7.30 (d, J=9.3 Hz, 2H), 7.34-7.41 (m, 4H),7.44-7.50 (m, 1H), 7.85 (s, 1H), 7.89 (d, J=8.0 Hz, 1H); m/z 492 [M+H]⁺,490 [M−H]⁻.

Compound 3:1-(benzenesulfonyl)-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea

Benzenesulfonyl isocyanate (23 μL, 0.170 mmol) was added to a solutionof2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethanamine(50 mg, 0.170 mmol) and CH₂Cl₂ (1 mL). After 30 minutes volatiles wereremoved, and the resulting residue was purified by silica gel columnchromatography, eluting with a gradient of 0 to 100% EtOAc in heptane.The title compound was obtained as a light tan solid (66 mg, 81%). ¹HNMR (400 MHz, CHLOROFORM-d): δ ppm 1.33 (t, J=7.6 Hz, 3H), 2.50 (s, 3H),2.85-2.96 (m, 4H), 3.04 (s, 3H), 3.56 (q, J=6.6 Hz, 2H), 7.35-7.39 (m,2H), 7.40-7.44 (m, 2H), 7.45-7.51 (m, 2H), 7.56-7.61 (m, 1H), 7.82-7.85(m, 2H); m/z 478 [M+H]⁺, 476 [M−H]⁻.

Compound 4:1-cyclopentylsulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea

Cyclopentylsulfonyl isocyanate (12 μL, 0.102 mmol) was added to asolution of2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethanamine(30 mg, 0.102 mmol) and CH₂Cl₂ (0.5 mL). After 36 hours volatiles wereremoved, and the resulting residue was purified by silica gel columnchromatography, eluting with a gradient of 0 to 100% EtOAc in heptane.The title compound was obtained as a light tan solid (30 mg, 63%). ¹HNMR (400 MHz, CHLOROFORM-d): δ ppm 1.32 (t, J=7.5 Hz, 3H), 1.60-1.67 (m,2H), 1.74-1.81 (m, 2H), 1.96-2.04 (m, 4H), 2.46 (s, 3H), 2.86 (q, J=7.5Hz, 2H), 2.94-2.99 (m, 5H), 3.57-3.64 (m, 2H), 3.69 (t, J=7.9 Hz, 1H),6.79 (t, J=6.1 Hz, 1H,) 7.36-7.40 (m, 2H), 7.40-7.44 (m, 2H), 7.73 (s,1H); m/z 470 [M+H]⁺, 468 [M−H]⁻.

Compound 5:1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-[4-(trifluoromethoxy)phenyl]sulfonyl-urea

4-Trifluoromethyl-benzenesulfonyl isocyanate (18 μL, 0.102 mmol) wasadded to a solution of2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethanamine(30 mg, 0.102 mmol) and CH₂Cl₂ (0.5 mL). After 36 hours volatiles wereremoved, and the resulting residue was purified by silica gel columnchromatography, eluting with a gradient of 0 to 100% EtOAc in heptane.The title compound was obtained as a light tan solid (37 mg, 65%). ¹HNMR (400 MHz, CHLOROFORM-d): δ ppm 1.33 (t, J=7.6 Hz, 3H), 2.50 (s, 3H),2.88 (q, J=7.6 Hz, 2H), 2.93 (t, J=6.5 Hz, 2H), 3.03 (s, 3H), 3.57 (q,J=6.4 Hz, 2H), 6.79 (br. s., 1H), 7.31 (d, J=8.1 Hz, 2H), 7.35-7.39 (m,2H), 7.40-7.44 (m, 2H), 7.83 (s, 1H), 7.91 (d, J=8.9 Hz, 2H); m/z 562[M+H]⁺, 560 [M−H]⁻.

Example 2 Compound 6:1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]ethyl]-3-(p-tolylsulfonyl)urea

Intermediate 1: tert-butyl N-[2-(5-bromo-2-pyridyl)ethyl]carbamate

Di-tert-butyl dicarboxylate (1.30 g, 5.96 mmol) was added to a stirredsolution of 2-(5-bromopyridin-2-yl)ethamine (1.00 g, 4.97 mmol),triethylamine (2.08 mL, 14.9 mmol), and CH₂Cl₂ (20 mL). After 18 hoursvolatiles were removed, and the resulting residue was purified by silicagel column chromatography, eluting with a gradient of 0 to 30% EtOAc inheptane. The title compound was recovered as an off-white solid (1.36 g,91%). ¹H NMR (400 MHz, CHLOROFORM-d): 5 ppm 1.43 (s, 9H), 3.00 (t, J=6.0Hz, 2H), 3.54 (br. s., 2H), 5.04 (br. s., 1H), 7.14 (d, J=8.2 Hz, 1H),7.79 (d, J=8.3 Hz, H), 8.61 (d, J=2.3 Hz, 1H); m/z 301 [⁷⁹Br+H]⁺, 303[⁸¹Br+H]⁺.

Intermediate 2: [6-[2-(tert-butoxycarbonylamino)ethyl]-3-pyridyl]boronicAcid

Bis(phosphino-ferrocene)dichloropalladium(0) dichloromethane complex(1:1) (111 mg, 0.136 mmol) was added to a stirred solution of tert-butylN-[2-(5-bromo-2-pyridyl)ethyl]carbamate (1.36 g, 4.52 mmol),Bis(pinacolate)diboron (1.38 g, 5.42 mmol), potassium acetate (1.33 g,13.6 mmol), and dioxane (23 mL). Air was evacuated and replaced withnitrogen three times. The solution was heated at 80° C. for 18 hoursbefore the solution was cooled, combined with EtOAc (25 mL), andfiltered through a pad of Celite. The filtrate was concentrated andpurified by reverse phase chromatography to provide the title compoundas a colorless residue (753 mg, 63%). m/z 267 [M+H]⁺.

Intermediate 3: tert-butylN-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]ethyl]carbamate

A 50 mL round bottom flask was charged with[6-[2-(tert-butoxycarbonylamino)ethyl]-3-pyridyl]boronic acid (508 mg,2.00 mmol), carbamic acid, [2-(5-borono-2-pyridinyl)ethyl]-,1,1-dimethylethyl ester (750 mg, 2.83 mmol), cesium carbonate (1.95 g,6.00 mmol), and dioxane (10 mL). Air was evacuated and replaced withnitrogen three times. Bis(phosphinoferrocene)dichloropalladium(0)dichoromethane complex (1:1) (163 mg, 0.20 mmol) was added last. Thesolution was heated at 80° C. for 18 hours before the reaction mixturewas cooled, diluted with EtOAc (30 mL), and filtered through a plug ofCelite. The filtrate was concentrated and purified by silica gel columnchromatography, eluting with 0 to 5% methanol in CH₂Cl₂ to give thetitle compound (460 mg). m/z 396 [M+H]⁺.

Intermediate 4:2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]ethanamine

Trifluoroacetic acid (1 mL) was added to a stirred solution oftert-butylN-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]ethyl]carbamate(460 mg, 1.16 mmol) and CH₂Cl₂ (12 mL) in an ice-water bath. Thesolution was permitted to warm to room temperature as it was stirredovernight. After 18 hours the reaction mixture was diluted with EtOAc(40 mL) and extracted with saturated, aqueous NaHCO₃ (1×10 mL) and brine(1×10 mL). The aqueous layers were combined, concentrated, and purifiedby reverse phase chromatography to provide the title compound as a darkresidue (157 mg, 46%). ¹H NMR (400 MHz, CHLOROFORM-d): b ppm 1.30 (t,J=7.52 Hz, 3H), 2.42 (s, 3H), 2.75-2.85 (m, 2H), 2.86-2.90 (m, 3H),3.12-3.18 (m, 1H), 3.29-3.39 (m, 1H), 7.38 (d, J=8.20 Hz, 1H), 7.60 (s,1H), 7.70 (dd, J=7.91, 2.24 Hz, 1H,) 8.56-8.64 (m, 1H); m/z 296 [M+H]⁺.

1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]ethyl]-3-(p-tolylsulfonyl)urea

4-Tolylsulfonyl isocyanate (26 μL, 0.169 mmol) was added to2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]ethanamine(50 mg, 0.169 mmol) and CH₂Cl₂ (1 mL). After 18 hours volatiles wereremoved, and the resulting residue was purified by silica gel columnchromatography, eluting with 0 to 10% CH₃OH in CH₂Cl₂ to provide thetitle compound as a white solid (39 mg, 47%). ¹H NMR (400 MHz,CHLOROFORM-d): δ ppm 1.34 (t, J=7.5 Hz, 3H), 2.41 (s, 3H) 2.45 (s, 3H),2.85 (q, J=7.5 Hz, 2H) 2.95 (s, 3H) 3.13 (t, J=6.3 Hz, 2H) 3.75 (q,J=6.0 Hz, 2H) 7.29 (s, 2H), 7.39 (d, J=7.9 Hz, 1H), 7.69 (s, 1H), 7.73(d, J=2.0 Hz, 1H), 7.77 (d, J=8.3 Hz, 2H), 8.68 (s, 1H); m/z 493 [M+H]⁺,491 [M−H]⁻.

Example 3 Compound 7:1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-thienyl]ethyl]-3-(p-tolylsulfonyl)urea

Intermediate 1: tert-butyl N-[2-(5-bromo-2-thienyl)ethyl]carbamate

2-(5-Bromothiophen-2-yl)ethan-1-amine (1.00 g, 4.85 mmol), di-tert-butyldicarboxylate (1.27 g, 5.82 mmol), triethylamine (2 mL, 14.6 mmol), andCH₂Cl₂ (24 mL) were combined and stirred at room temperature for 18hours before volatiles were removed, and the resulting residue waspurified by silica gel column chromatography, eluting with a gradient of0 to 30% EtOAc in heptane to give the title compound as a colorless oil(1.48 g, 99%). ¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.45 (s, 9H), 2.95(t, J=6.6 Hz, 2H), 3.36 (d, J=5.8 Hz, 2H), 4.65 (br. s., 1H), 6.60 (d,J=3.7 Hz, 1H), 6.89 (d, J=3.7 Hz, 1H); m/z 250 [M-(t-Bu)+H]⁺.

Intermediate 2: tert-butylN-[2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]ethyl]carbamate

tert-Butyl N-[2-(5-bromo-2-thienyl)ethyl]carbamate (1.48 g, 4.83 mmol),Bis(pinacolate)diboron (1.47 g, 5.80 mmol), potassium acetate (1.42 g,14.5 mmol), and dioxane (50 mL) were combined; air was evacuated andreplaced with nitrogen three times.Bis(phosphinoferrocene)dichloro-palladium(0) dichloromethane complex(1:1) (118 mg, 0.145 mmol) was added last, and the reaction mixture washeated at 80° C. for 18 hours before the solution was cooled, dilutedwith EtOAc (50 mL), and filtered through a pad of Celite. The filtratewas concentrated and purified by silica gel column chromatography,eluting with a gradient of 0 to 40% EtOAc in heptane to give the titlecompound as a colorless oil (419 mg, 25%). ¹H NMR (400 MHz,CHLOROFORM-d): δ ppm 1.34 (s, 12H), 1.44 (s, 9H), 3.06 (t, J=6.5 Hz,2H), 3.42 (d, J=5.5 Hz, 2H), 4.66 (br. s., 1H) 6.92 (d, J=3.4 Hz, 1H),7.50 (d, J=3.4 Hz, 1H); m/z 298 [M-(t-Bu)+H]⁺.

Intermediate 3: tert-butylN-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-thienyl]ethyl]carbamate

tert-ButylN-[2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]ethyl]carbamate(412 mg, 1.12 mmol), 3-bromo-2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazine(254 mg, 1.00 mmol), cesium carbonate (977 mg, 3.00 mmol), and dioxane(5 mL) were combined. Air was evacuated and replaced with nitrogen threetimes. Bis(phosphinoferrocene)dichloropalladium(0) dichloromethanecomplex (1:1) (82 mg, 0.10 mmol) was added last, and the solution washeated at 80° C. for 18 hours before the reaction mixture was cooled,diluted with EtOAc (10 mL), and filtered through a pad of Celite. Thefiltrate was concentrated and purified by silica gel columnchromatography, eluting with a gradient of 0 to 100% EtOAc in heptane togive the title compound as an amber oil (275 mg, 69%). ¹H NMR (400 MHz,CHLOROFORM-d): δ ppm 1.33 (t, J=7.6 Hz, 3H), 1.47 (s, 9H), 2.47 (s, 3H),2.85-2.93 (m, 5H), 3.09 (t, J=6.8 Hz, 2H), 3.48 (d, J=6.3 Hz, 2H), 4.75(br. s., 1H), 6.96 (d, J=3.5 Hz, 1H), 7.04 (d, J=3.5 Hz, 1H), 7.80 (s,1H); m/z 401 [M+H]⁺.

Intermediate 4:2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-thienyl]ethanamine

Trifluoroacetic acid (524 μL, 6.84 mmol) was added slowly, dropwise to astirred solution of tert-butylN-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-thienyl]ethyl]carbamate(274 mg, 0.684 mmol) and CH₂Cl₂ (7 mL) in an ice-water bath. After 18hours volatiles were removed, and the resulting residue was dissolved inEtOAc (40 mL), washed with saturated aqueous NaHCO₃ (1×10 mL), washedwith brine (1×10 mL), dried (Na₂SO₄), filtered, and concentrated to givethe title compound as a dark solid (143 mg, 69%). ¹H NMR (400 MHz,METHANOL-d4): δ ppm 1.28 (t, J=7.61 Hz, 3H), 2.42 (d, J=0.78 Hz, 3H),2.80 (s, 3H), 2.85 (q, J=7.61 Hz, 2H), 3.09-3.27 (m, 4H), 7.11 (d,J=3.51 Hz, 1H), 7.20 (d, J=3.71 Hz, 1H), 7.96 (s, 1H); m/z 301 [M+H]⁺.

1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-thienyl]ethyl]-3-(p-tolylsulfonyl)urea

4-Tolylsulfonyl isocyanate (26 μL, 0.166 mmol) was added to a mixture of2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-thienyl]ethanamine(50 mg, 0.166 mmol) and CH₂Cl₂ (1 mL). After 30 minutes volatiles wereremoved, and the resulting residue was purified by silica gel columnchromatography, eluting with a gradient of 0 to 100% EtOAc in heptane togive the title compound as a yellow solid (46 mg, 55%). ¹H NMR (400 MHz,CHLOROFORM-d): δ ppm 1.33 (t, J=7.61 Hz, 3H), 2.39 (s, 3H), 2.45 (s,3H), 2.85-2.95 (m, 5H), 3.12 (t, J=6.64 Hz, 2H), 3.61 (q, J=6.51 Hz,2H), 6.85 (br s, 1H), 6.97 (d, J=3.51 Hz, 1H), 7.06 (d, J=3.51 Hz, 1H),7.27 (br d, J=8.00 Hz, 3H), 7.72 (d, J=8.20 Hz, 2H), 7.82 (s, 1H); m/z498 [M+H]⁺, 496 [M−H]⁻.

Example 4 Compound 8:1-[2-[4-(6,8-dichloro-2-ethyl-imidazo[1,2-a]pyridin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea

Intermediate 2: 6,8-dichloro-2-ethyl-imidazo[1,2-a]pyridine

Dissolved 3,5-dichloropyridin-2-amine (500 mg, 3.07 mmol) in t-BuOH (5mL). Added 1-bromo-2-butanone (0.47 mL, 4.59 mmol). Heated the reactionto 80° C. and stirred for 16 hours. Removed solvent and brought upresidue in NaHCO₃ (70 mL). Extracted with EtOAc (3×70 mL). Combinedorganics and washed with brine. Dried over Na₂SO₄. Filtered and removedsolvent. Purified using normal phase chromatography (0-100% EtOAc inHeptanes) to yield 450 mg product. ¹H NMR (400 MHz, CHLOROFORM-d)δ=8.12-7.98 (m, 1H), 7.39 (s, 1H), 7.25-7.16 (m, 1H), 2.87 (q, J=7.5 Hz,2H), 1.41-1.30 (m, 3H); LCMS (M/Z): 163.0 (M+H).

Intermediate 2: 3-bromo-6,8-dichloro-2-ethyl-imidazo[1,2-a]pyridine

Brought up 6,8-dichloro-2-ethyl-imidazo[1,2-a]pyridine (450 mg, 2.09mmol) in acetic acid (10 mL). Slowly added bromine (107 μL, 2.09 mmol)and stirred for 30 minutes. Concentrated via vacuum and diluted with H₂O(50 mL). Adjusted pH to ˜8 using NaHCO₃ (sat'd). Extracted with EtOAc(3×50 mL). Washed with brine and dried over Na₂SO₄. Filtered and removedsolvent to yield 550 mg of crude product; LCMS (M/Z): 295.0 (M+H).

1-[2-[4-(6,8-dichloro-2-ethyl-imidazo[1,2-a]pyridin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea

Brought up 3-bromo-6,8-dichloro-2-ethyl-imidazo[1,2-a]pyridine (190 mg,0.646 mmol) and1-(p-tolylsulfonyl)-3-[2-[4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl]ethyl]urea(430 mg, 0.968 mmol) in 1,4-Dioxane (5 mL). Charged with[1,1′-Bis(diphenylphosphino) ferrocene]palladium(II) dichloride (52 mg,10 mol %) and Cs₂CO₃ (630 mg, 1.94 mmol). Heated to 80° C. for 16 hours.Purified using reverse phase chromatography (0-100% MeOH in H₂O) toyield 26 mg product. ¹H NMR (400 MHz, DMSO-d6) δ=8.16 (d, J=1.4 Hz, 1H),7.82-7.72 (m, 2H), 7.61 (d, J=1.6 Hz, 1H), 7.47-7.40 (m, 2H), 7.39-7.30(m, 4H), 3.31-3.16 (m, 4H), 2.82-2.61 (m, 4H), 2.34 (s, 3H), 1.22 (t,J=7.5 Hz, 3H); LCMS (M/Z): 531.0 (M+H).

Example 5 Compound 9:1-[2-[4-(6-cyano-2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea

Intermediate 1: 2-ethyl-8-methyl-imidazo[1,2-a]pyrazine-6-carbonitrile

Dissolved 5-amino-6-methyl-pyrazine-2-carbonitrile (500 mg, 3.73 mmol)in t-BuOH (5 mL). Added 1-bromo-2-butanone (0.57 mL, 3.73 mmol). Heatedthe reaction to 100° C. and stirred for 16 hours. Removed solvent andbrought up residue in NaHCO₃ (40 mL). Extracted with EtOAc (3×40 mL).Combined organics and washed with brine. Dried over Na₂SO₄. Filtered andremoved solvent. Purified using normal phase chromatography (0-100%EtOAc in Heptanes) to yield 285 mg product. LCMS (M/Z): 187.2 (M+H).

Intermediate 2:3-bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyrazine-6-carbonitrile

Brought up 2-ethyl-8-methyl-imidazo[1,2-a]pyrazine-6-carbonitrile (285mg, 1.53 mmol) in acetic acid (5 mL). Slowly added bromine (78 μL, 1.53mmol) and stirred for 30 minutes. Concentrated via vacuum and dilutedwith H₂O (50 mL). Adjusted pH to 8 using NaHCO₃ (sat'd). Extracted withEtOAc (3×50 mL). Washed with brine and dried over Na₂SO₄. Filtered andremoved solvent. Purified using normal phase chromatography (0-10% MeOHin DCM) to yield 300 mg of crude product; ¹H NMR (400 MHz, METHANOL-d4)δ=9.00-8.78 (m, 1H), 3.00-2.73 (m, 5H), 1.37 (t, J=7.6 Hz, 3H); LCMS(M/Z): 265.0 (M+H).

1-[2-[4-(6-cyano-2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea

Brought up3-bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyrazine-6-carbonitrile (300 mg,1.13 mmol) and1-(p-tolylsulfonyl)-3-[2-[4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl]ethyl]urea(703 mg, 1.58 mmol) in 1,4-Dioxane (15 mL). Charged with[1,1′-Bis(diphenylphosphino) ferrocene] palladium(II) dichloride (136mg, 10 mol %) and Cs₂CO₃ (1.63 g, 5.00 mmol). Heated to 80° C. for 16hours. Purified using reverse phase chromatography (0-100% MeOH in H₂O)to yield 2.2 mg of product. ¹H NMR (400 MHz, METHANOL-d4) δ=8.65 (s,1H), 7.83 (d, J=8.4 Hz, 2H), 7.45 (s, 4H), 7.37 (d, J=8.2 Hz, 2H), 3.45(t, J=7.0 Hz, 2H), 2.95-2.78 (m, 7H), 2.39 (s, 3H), 1.32 (t, J=7.5 Hz,3H); LCMS (M/Z): 503.2 (M+H).

Example 6 Compound 10:1-[2-[4-(2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea

Intermediate 1: 2-ethyl-8-methyl-imidazo[1,2-a]pyrazine

Dissolved 3-methylpyrazin-2-amine (500 mg, 4.58 mmol) in t-BuOH (5 mL).Added 1-bromo-2-butanone (0.66 mL, 6.41 mmol). Heated the reaction to80° C. and stirred for 16 hours. Removed solvent and brought up residuein NaHCO₃ (40 mL). Extracted with EtOAc (3×40 mL). Combined organics andwashed with brine. Dried over Na₂SO₄. Filtered and removed solvent.Purified using normal phase chromatography (0-100% EtOAc in Heptanes) toyield 512 mg product. LCMS (M/Z):162.2 (M+H).

Intermediate 2: 3-bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyrazine

Brought up 2-ethyl-8-methyl-imidazo[1,2-a]pyrazine (513 mg, 3.18 mmol)in acetic acid (5 mL). Slowly added bromine (163 μL, 3.18 mmol) andstirred for 30 minutes. Concentrated via vacuum and diluted with H₂O (50mL). Adjusted pH to ˜8 using NaHCO₃ (sat'd). Extracted with EtOAc (3×50mL). Washed with brine and dried over Na₂SO₄. Filtered and removedsolvent. Purified using normal phase chromatography (0-10% MeOH in DCM)to yield 400 mg of crude product; ¹H NMR (400 MHz, METHANOL-d4)δ=8.36-8.03 (m, 1H), 7.96-7.61 (m, 1H), 3.05-2.68 (m, 5H), 1.36 (t,J=7.6 Hz, 3H).

1-[2-[4-(2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea

Brought up 3-bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyrazine (400 mg, 1.67mmol) and1-(p-tolylsulfonyl)-3-[2-[4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl]ethyl]urea(887 mg, 2.00 mmol) in 1,4-Dioxane (15 mL). Charged with[1,1′-Bis(diphenylphosphino) ferrocene]palladium(II) dichloride (136 mg,10 mol %) and Cs₂CO₃ (1.63 g, 5.00 mmol). Heated to 80° C. for 16 hours.Purified using reverse phase chromatography (0-100% MeOH in H₂O) toyield 2.0 mg of product. ¹H NMR (400 MHz, METHANOL-d4) δ=8.01 (d, J=4.7Hz, 1H), 7.78 (d, J=8.2 Hz, 2H), 7.67 (d, J=4.7 Hz, 1H), 7.38 (s, 4H),7.31 (d, J=8.2 Hz, 2H), 3.40 (t, J=7.0 Hz, 2H), 2.95-2.72 (m, 7H), 2.33(s, 3H), 1.28 (t, J=7.5 Hz, 3H); LCMS (M/Z): 478.2 (M+H).

Example 7 Compound 11:1-[2-[4-(2-ethyl-8-methyl-6-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea

Intermediate 1: 6-bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyrazine

Dissolved 5-bromo-3-methyl-pyrazin-2-amine (2.0 g, 10.64 mmol) in t-BuOH(40 mL). Added 1-bromo-2-butanone (1.64 mL, 16.0 mmol). Heated thereaction to 80° C. and stir for 16 hours. Removed solvent and brought upresidue in NaHCO₃ (40 mL). Extracted with EtOAc (3×40 mL). Combinedorganics and washed with brine. Dried over Na₂SO₄. Filtered and removedsolvent. Purified using normal phase chromatography (0-10% MeOH in DCM)to yield 2.50 g product. LCMS (M/Z): 240.0 (M+H).

Intermediate 2: 2-ethyl-8-methyl-6-phenyl-imidazo[1,2-a]pyrazine

Brought up 6-bromo-2-ethyl-8-methyl-imidazo[1,2-a] pyrazine (250 mg,1.04 mmol) and phenylboronic acid pinacol ester (318 mg, 1.56 mmol) in1,4-Dioxane (5 mL). Charged with [1,1′-Bis(diphenylphosphino) ferrocene]palladium(II) dichloride 85 mg, 10 mol %) and Cs₂CO₃ (1.02 g, 3.12mmol). Heated to 80° C. for 16 hours. Purified using reverse phasechromatography (0-100% EtOAc in Heptanes) to yield 150 mg of product. ¹HNMR (400 MHz, METHANOL-d4) δ=8.77-8.63 (m, 1H), 8.05-7.92 (m, 2H),7.88-7.77 (m, 1H), 7.54-7.45 (m, 2H), 7.45-7.37 (m, 1H), 2.98-2.80 (m,5H), 1.40 (t, J=7.6 Hz, 3H); LCMS (M/Z): 238.2 (M+H).

Intermediate 3: 3-bromo-2-ethyl-8-methyl-6-phenyl-imidazo[1,2-a]pyrazine

Brought up 2-ethyl-8-methyl-6-phenyl-imidazo[1,2-a] pyrazine (240 mg,1.01 mmol) in acetic acid (5 mL). Slowly added bromine (52 μL, 1.01mmol) and stirred for 30 minutes. Concentrated via vacuum and dilutedwith H₂O (50 mL). Adjusted pH to ˜8 using NaHCO₃ (sat'd). Extracted withEtOAc (3×50 mL). Washed with brine and dried over Na₂SO₄. Filtered andremoved solvent. Purified using normal phase chromatography (0-10% MeOHin DCM) to yield 164 mg of product; LCMS (M/Z): 318.0 (M+H).

1-[2-[4-(2-ethyl-8-methyl-6-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea

Brought up 3-bromo-2-ethyl-8-methyl-6-phenyl-imidazo[1,2-a]pyrazine 154mg, 0.489 mmol) and1-(p-tolylsulfonyl)-3-[2-[4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl]ethyl]urea(325 mg, 0.732 mmol) in 1,4-Dioxane (4 mL). Charged with[1,1′-Bis(diphenylphosphino) ferrocene] palladium(II) dichloride 38 mg,10 mol %) and Cs₂CO₃ 477 mg, 1.46 mmol). Heated to 80° C. for 16 hours.Purified using reverse phase chromatography (0-100% MeOH in H₂O) toyield 1.0 mg of product. ¹H NMR (400 MHz, METHANOL-d4) δ=8.32-8.19 (m,1H), 7.91-7.84 (m, 2H), 7.81-7.74 (m, 2H), 7.53-7.35 (m, 7H), 7.33-7.23(m, 2H), 3.55-3.42 (m, 2H), 2.95 (s, 7H), 2.33 (s, 3H), 1.34 (s, 5H);LCMS (M/Z): 554.2 (M+H).

Compound 12:1-[2-[4-[2-ethyl-8-methyl-6-(3-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea

1-[2-[4-[2-ethyl-8-methyl-6-(3-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea

Brought up 3-bromo-2-ethyl-8-methyl-6-(3-pyridyl)imidazo[1,2-a]pyrazine(164 mg, 0.517 mmol) and1-(p-tolylsulfonyl)-3-[2-[4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl]ethyl]urea275 mg, 0.619 mmol) in 1,4-Dioxane (4 mL). Charged with[1,1′-Bis(diphenylphosphino) ferrocene]palladium (II) dichloride 42 mg,10 mol %) and Cs₂CO₃ 505 g, 1.55 mmol). Heated to 80° C. for 16 hours.Purified using reverse phase chromatography (0-100% MeOH in H₂O) toyield 25.0 mg of product. ¹H NMR (400 MHz, METHANOL-d4) δ=9.11 (s, 1H),8.55 (br s, 1H), 8.40 (s, 1H), 8.37-8.30 (m, 1H), 7.78 (d, J=8.4 Hz,2H), 7.56-7.41 (m, 5H), 7.32 (d, J=8.2 Hz, 2H), 3.48 (t, J=6.8 Hz, 2H),2.96 (s, 3H), 2.93-2.81 (m, 4H), 2.35 (s, 3H), 1.34 (t, J=7.5 Hz, 3H);LCMS (M/Z): 555.2 (M+H).

Compound 13:1-[2-[4-[2-ethyl-8-methyl-6-(4-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea

1-[2-[4-[2-ethyl-8-methyl-6-(4-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea

Brought up 3-bromo-2-ethyl-8-methyl-6-(4-pyridyl)imidazo[1,2-a]pyrazine(296 mg, 0.935 mmol) and1-(p-tolylsulfonyl)-3-[2-[4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl]ethyl]urea498 mg, 1.12 mmol) in 1,4-Dioxane (4 mL). Charged with[1,1′-Bis(diphenylphosphino) ferrocene]palladium(II) dichloride 76 mg,10 mol %) and Cs₂CO₃ 913 mg, 2.80 mmol). Heated to 80° C. for 16 hours.Purified using reverse phase chromatography (0-100% MeOH in H₂O) toyield 40 mg of product. ¹H NMR (400 MHz, METHANOL-d4) δ=8.55 (br d,J=5.9 Hz, 2H), 8.50 (s, 1H), 7.98 (br d, J=6.2 Hz, 2H), 7.77 (d, J=8.2Hz, 2H), 7.56-7.42 (m, 4H), 7.32 (d, J=8.2 Hz, 2H), 3.49 (t, J=6.8 Hz,2H), 3.01-2.73 (m, 7H), 2.34 (s, 3H), 1.34 (t, J=7.6 Hz, 3H); LCMS(M/Z): 555.2 (M+H).

Compound 14:1-[2-[4-(6,8-dimethyl-2-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea

Followed procedures analogous to those in previous examples. Then,3-bromo-6,8-dimethyl-2-phenyl-imidazo[1,2-a]pyrazine (0.5 mmol, 150.5mg) and1-(p-tolylsulfonyl)-3-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]urea(0.75 mmol, 333.0 mg) were taken in dioxane (5.0 ml) and water (2.0 ml)and the solution was degassed for 3 min. A degassed solution of cesiumcarbonate (1.5 mmol, 487.0 mg) in water (2.0 ml) was added followed byPd(dppf)₂Cl₂:DCM (81.6 mg). The mixture was degassed again for 5 min andthe reaction was stirred at 80° C. for 2 h. LC-MS indicated completionof reaction. The reaction was cooled and diluted with ethylacetate (20ml) and filtered through a pad of celite and florisil (100-200 Mesh) andconcentrated. The crude was purified on silica gel using heptane/ethylacetate to give 202 mg (0.375 mmol, 65%) of the desired product. LC-MS540 (M+H); ¹H NMR (400 MHz, METHANOL-d4) δ ppm 2.29-2.45 (m, 6H)2.79-3.04 (m, 5H) 3.47-3.64 (m, 2H) 6.45-6.72 (m, 1H) 7.16-7.43 (m, 9H)7.56-7.80 (m, 6H)

Compound 15:1-[2-[4-(2-isoxazol-3-yl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea

Followed procedures analogous to those in previous examples. Then,3-(3-bromo-6,8-dimethyl-imidazo[1,2-a]pyrazin-2-yl)isoxazole (0.5 mmol,146.0 mg) and1-(p-tolylsulfonyl)-3-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]urea(0.75 mmol, 333.0 mg) were taken in dioxane (5.0 ml) and water (2.0 ml)and the solution was degassed for 3 min. A degassed solution of cesiumcarbonate (1.5 mmol, 487.0 mg) in water (2.0 ml) was added followed byPd(dppf)₂Cl₂:DCM (81.6 mg). The mixture was degassed again for 5 min andthe reaction was stirred at 80° C. for 2 h. LC-MS indicated completionof reaction. The reaction was cooled and diluted with ethylacetate (20ml) and filtered through celite and concentrated. The crude was purifiedon silica gel using heptane/ethyl acetate to give 63.6 mg (0.12 mmol,24%) of the desired product. LC-MS 531 (M+H); ¹H NMR (400 MHz, DMSO-d6)δ ppm 2.27-2.37 (m, 7H) 2.70-2.83 (m, 5H) 6.59 (br. s., 1H) 7.24-7.54(m, 6H) 7.66-8.04 (m, 3H) 8.92 (d, J=1.71 Hz, 1H).

Compound 16:1-[2-[4-(6,8-dimethyl-2-tetrahydrofuran-3-yl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea

Followed procedures analogous to those in previous examples. Then,3-bromo-6,8-dimethyl-2-tetrahydrofuran-3-yl-imidazo[1,2-a]pyrazine (0.5mmol, 147.5 mg) and1-(p-tolylsulfonyl)-3-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]urea(0.75 mmol, 333.0 mg) were taken in dioxane (5.0 ml) and water (2.0 ml)and the solution was degassed for 3 min. A degassed solution of cesiumcarbonate (1.5 mmol, 487.0 mg) in water (2.0 ml) was added followed byPd(dppf)₂Cl₂:DCM (81.6 mg). The mixture was degassed again for 5 min andthe reaction was stirred at 80° C. for 2 h. LC-MS indicated completionof reaction. The reaction was cooled and diluted with ethylacetate (20ml) and filtered through celite and concentrated. The crude was purifiedon silica gel using heptane/ethyl acetate to give 31.9 mg (0.06 mmol,12%) of the desired product. LC-MS 534 (M+H); ¹H NMR (400 MHz,DICHLOROMETHANE-d2) δ ppm 2.27-2.51 (m, 9H) 2.80 (s, 4H) 2.90 (t, J=6.93Hz, 2H) 3.44-3.62 (m, 3H) 3.73-3.96 (m, 2H) 3.96-4.12 (m, 2H) 7.28-7.43(m, 6H) 7.57-7.80 (m, 4H).

Compound 17:1-[2-[4-(2-ethyl-6,8-difluoro-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea

Followed procedures analogous to those in previous examples. Then,3-bromo-2-ethyl-6,8-difluoro-imidazo[1,2-a]pyrazine (0.5 mmol, 130.5 mg)and1-(p-tolylsulfonyl)-3-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]urea(0.75 mmol, 333.0 mg) were taken in dioxane (5.0 ml) and water (2.0 ml)and the solution was degassed for 3 min. A degassed solution of cesiumcarbonate (1.5 mmol, 487.0 mg) in water (2.0 ml) was added followed byPd(dppf)₂Cl₂:DCM (81.6 mg). The mixture was degassed again for 5 min andthe reaction was stirred at 80° C. for 2 h. LC-MS indicated completionof reaction. The reaction was cooled and diluted with ethylacetate (20ml) and filtered through celite and concentrated. The crude was purifiedon silica gel using heptane/ethyl acetate to give 27.4 mg (0.055 mmol,11%) of the desired product. LC-MS 499 (M+H); ¹H NMR (400 MHz, DMSO-d6)δ ppm 1.21 (t, J=7.52 Hz, 3H) 2.33 (s, 3H) 2.59-2.86 (m, 4H) 6.33-6.56(m, 1H) 7.28-7.50 (m, 7H) 7.67-7.79 (m, 2H) 8.12 (dd, J=4.17, 1.78 Hz,1H) 10.56 (s, 1H).

Compound 18:1-[2-[4-[6,8-dimethyl-2-(1-methylsulfonyl-4-piperidyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea

Followed procedures analogous to those in previous examples. Then,tert-butyl4-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)piperidine-1-carboxylate (3.0mmol, 990 mg) was dissolved THF (10.0 mL) and 4M HCl in 1,4-dioxane (5.0mL) was added and the mixture was stirred at room temperature for 16 h.LCMS indicated completion of reaction. The solvent was removed undervacuum at room temperature. The crude was dissolved in DCM (15.0 mL) andTriethylamine (2.0 mL) was added at 0° C. followed by methane sulfonylchloride. The mixture was stirred at 0-25° C. for 2 h. Diluted with DCM(50.0 mL), washed with water (10.0 mL) and a solution of saturatedNaHCO₃ (10.0 mL). The organic layer was dried over anhydrous MgSO₄ andconcentrated to give desired compound. This was carried forward withoutany further purification.

Followed procedures analogous to those in previous examples to make thekey intermediate. Then,3-bromo-6,8-dimethyl-2-(1-methylsulfonyl-4-piperidyl)imidazo[1,2-a]pyrazine(0.5 mmol, 193.0 mg) and1-(p-tolylsulfonyl)-3-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]urea(0.75 mmol, 333.0 mg) were taken in dioxane (5.0 ml) and water (2.0 ml)and the solution was degassed for 3 min. A degassed solution of cesiumcarbonate (1.5 mmol, 487.0 mg) in water (2.0 ml) was added followed byPd(dppf)₂Cl₂:DCM (81.6 mg). The mixture was degassed again for 5 min andthe reaction was stirred at 80° C. for 2 h. LC-MS indicated completionof reaction. The reaction was cooled and diluted with ethylacetate (20ml) and filtered through celite and concentrated. The crude was purifiedon silicagel using heptane/ethyl acetate to give 24.9 mg (0.04 mmol,16%) of the desired product. LC-MS 625 (M+H); ¹H NMR (400 MHz,METHANOL-d4) δ ppm 1.75-1.90 (m, 2H) 1.99-2.14 (m, 2H) 2.35 (d, J=8.44Hz, 6H) 2.65-2.99 (m, 10H) 3.42 (t, J=6.96 Hz, 2H) 3.76 (d, J=11.76 Hz,2H) 7.19-7.48 (m, 6H) 7.63-7.86 (m, 3H).

Evaluation

The biological activity of compounds of the present disclosure wastested using the test methods described below.

Compounds were assayed at Eurofins Cerep using the human EP4 receptorantagonist screen. Cellular antagonist effect was calculated as a %inhibition of control reference agonist response for each target (PGE2).In each EP4(h) experiment, a reference antagonist compound, GW627368X,was tested concurrently with the test compounds, and the data werecompared with historical values determined at Eurofins. The experimentswere accepted in accordance with Eurofins validation Standard OperatingProcedure.

Detec- Incu- Measured tion Assay Source Stimulus bation Component MethodReceptors EP₄(h) Human PGE₂ 10 cAMP HTRF recombinant min (antagonist(CHO cells) (30 RT effect) nM)

The results are provided: the compounds of the disclosure generally havegreater than 50% inhibition at 1000 nM. Preferred compounds of thedisclosure, such as compounds 1, 2, 13, and 15, have about 50% orgreater inhibition at 100 nM.

All publications, patents, and patent applications cited in thisspecification are incorporated herein by reference for the teaching towhich such citation is used.

Test compounds for the experiments described herein were employed infree or salt form.

The specific responses observed may vary according to and depending onthe particular active compound selected or whether there are presentcarriers, as well as the type of formulation and mode of administrationemployed, and such expected variations or differences in the results arecontemplated in accordance with practice of the present disclosure.

Although specific embodiments of the present disclosure are hereinillustrated and described in detail, the disclosure is not limitedthereto. The above detailed descriptions are provided as exemplary ofthe present disclosure and should not be construed as constituting anylimitation of the disclosure. Modifications will be obvious to thoseskilled in the art, and all modifications that do not depart from thespirit of the disclosure are intended to be included with the scope ofthe appended claims.

That which is claimed is:
 1. A compound of Formula (II), or aveterinary, or pharmaceutically acceptable salt thereof: wherein

X is N or CR¹, where each R¹ individually is hydrogen, halogen, CN, C₁₋₃alkyl, or C₁₋₃ haloalkyl; R² is hydrogen, halogen, C₁₋₃ alkyl, C₁₋₃haloalky, CN, aryl, or heteroaryl; R³ is hydrogen, halogen, C₁₋₃ alkyl,C₁₋₃ haloalkyl or CN; R⁴ is hydrogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₃₋₆cycloalkyl, heterocyclyl, heteroaryl, or aryl; Z is phenyl or C₆₋₇cycloalkyl, each substituted with one or more R⁵, where R⁵ is hydrogen,halogen, CN, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, or C₁₋₃alkoxy; Ar is phenyl, pyridyl, or thiophenyl, each optionallysubstituted with one or more halogen, CN, NO₂, NH₂, N(C₁₋₃ alkyl)₂, OH,C₁₋₃ alkoxy, C₁₋₃ alkyl, or C₁₋₃ haloalkyl; L is —CH₂CH₂—, —CH₂CH₂CH₂—,or —OCH₂CH₂—; and n is 0 or
 1. 2. The compound of claim 1, wherein: a)Ar is phenyl and the group L is arranged para to the depictedimidazopyridine/pyrazine core; b) Ar is pyridyl and the group L isarranged para to the depicted imidazopyridine/pyrazine core; or c) Ar isthiophene and the group L is arranged 2,4, 2,5, or 3,5 to the depictedimidazopyridine/pyrazine core.
 3. The compound of claim 1, wherein X isN.
 4. The compound of claim 1, wherein R² is C₁₋₃ alkyl.
 5. The compoundof claim 1, wherein R³ is C₁₋₃ alkyl.
 6. The compound of claim 1,wherein R⁴ is C₁₋₃ alkyl or C₁₋₃ haloalkyl.
 7. The compound of claim 1,wherein R⁵ is C₁₋₃ alkyl or halogen.
 8. The compound of claim 1, whereinR⁵ is CH₃, F, or Cl.
 9. The compound of claim 1, wherein Ar is phenyl.10. The compound of claim 1, wherein Ar is 1,4-phenyl.
 11. The compoundof claim 10, wherein Ar is unsubstituted or substituted at one or moreof 2 and 3 positions.
 12. The compound of claim 1, wherein L is—CH₂CH₂—.
 13. The compound of claim 1, wherein n is
 0. 14. The compoundof claim 1, wherein n is
 1. 15. A compound selected from: a)1-(4-chlorophenyl)sulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;b)1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(o-tolylsulfonyl)urea;c)1-(benzenesulfonyl)-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;d)1-cyclopentylsulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;e)1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-[4-(trifluoromethoxy)phenyl]sulfonyl-urea;f)1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]ethyl]-3(p-tolylsulfonyl)urea;g)1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-thienyl]ethyl]-3-(p-tolylsulfonyl)urea;h)1-[2-[4-(6,8-dichloro-2-ethyl-imidazo[1,2-a]pyridin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;i)1-[2-[4-(6-cyano-2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;j)1-[2-[4-(2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea; k)1-[2-[4-(2-ethyl-8-methyl-6-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;l)1-[2-[4-[2-ethyl-8-methyl-6-(3-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;m)1-[2-[4-[2-ethyl-8-methyl-6-(4-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;n)1-[2-[4-(6,8-dimethyl-2-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;o)1-[2-[4-(2-isoxazol-3-yl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;p)1-[2-[4-(6,8-dimethyl-2-tetrahydrofuran-3-yl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;q)1-[2-[4-(2-ethyl-6,8-difluoro-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;and r)1-[2-[4-[6,8-dimethyl-2-(1-methylsulfonyl-4-piperidyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea,or a veterinary, or pharmaceutically acceptable salt thereof.
 16. Acomposition comprising a compound of claim 1, and a pharmaceutically orveterinary acceptable carrier.
 17. A combination comprising a compoundof claim 1, and one or more other pharmaceutically or veterinary activesubstances.
 18. A method for treating pain comprising administering to asubject in need thereof an effective amount of a compound of claim 1.19. The method of claim 18, wherein the subject is a mammal.
 20. Themethod of claim 19, where in the mammal is a companion animal.
 21. Themethod of claim 18, wherein the pain is associated with one or more ofjoint pain, musculoskeletal pain, lower back pain, neck pain, skeletalpain, sprain, strain, myositis, neuralgia, fibromyalgia, synovitis,arthritis, rheumatoid arthritis, degenerative joint disease,osteoarthritis, gout, ankylosing spondylitis, and bursitis.
 22. Acomposition comprising a) a compound selected from: (1)1-(4-chlorophenyl)sulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;(2)1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(o-tolylsulfonyl)urea;(3)1-(benzenesulfonyl)-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;(4)1-cyclopentylsulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;(5)1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-[4-(trifluoromethoxy)phenyl]sulfonyl-urea;(6)1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]ethyl]-3-(p-tolylsulfonyl)urea;(7)1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-thienyl]ethyl]-3-(p-tolylsulfonyl)urea;(8)1-[2-[4-(6,8-dichloro-2-ethyl-imidazo[1,2-a]pyridin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;(9)1-[2-[4-(6-cyano-2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;(10)1-[2-[4-(2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;(11)1-[2-[4-(2-ethyl-8-methyl-6-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;(12)1-[2-[4-[2-ethyl-8-methyl-6-(3-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;(13)1-[2-[4-[2-ethyl-8-methyl-6-(4-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;(14)1-[2-[4-(6,8-dimethyl-2-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;(15)1-[2-[4-(2-isoxazol-3-yl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;(16)1-[2-[4-(6,8-dimethyl-2-tetrahydrofuran-3-yl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;(17)1-[2-[4-(2-ethyl-6,8-difluoro-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;and (18)1-[2-[4-[6,8-dimethyl-2-(1-methylsulfonyl-4-piperidyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;or a veterinary, or pharmaceutically acceptable salt thereof; and b) oneor more veterinary or pharmaceutically acceptable carrier.
 23. A methodfor treating pain comprising administering to a subject in need thereofan effective amount of a compound selected from: i)1-(4-chlorophenyl)sulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;ii)1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(o-tolylsulfonyl)urea;iii)1-(benzenesulfonyl)-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;iv)1-cyclopentylsulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;v)1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-[4-(trifluoromethoxy)phenyl]sulfonyl-urea;vi)1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]ethyl]-3-(p-tolylsulfonyl)urea;vii)1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-thienyl]ethyl]-3-(p-tolylsulfonyl)urea;viii)1-[2-[4-(6,8-dichloro-2-ethyl-imidazo[1,2-a]pyridin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;ix)1-[2-[4-(6-cyano-2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;x)1-[2-[4-(2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;xi)1-[2-[4-(2-ethyl-8-methyl-6-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;xii)1-[2-[4-[2-ethyl-8-methyl-6-(3-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;xiii)1-[2-[4-[2-ethyl-8-methyl-6-(4-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;xiv)1-[2-[4-(6,8-dimethyl-2-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;xv)1-[2-[4-(2-isoxazol-3-yl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;xvi)1-[2-[4-(6,8-dimethyl-2-tetrahydrofuran-3-yl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;xvii)1-[2-[4-(2-ethyl-6,8-difluoro-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;and xviii)1-[2-[4-[6,8-dimethyl-2-(1-methylsulfonyl-4-piperidyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea,or a veterinary, or pharmaceutically acceptable salt thereof.